Open Access
Review
Issue
BioMedicine
Volume 7, Number 4, December 2017
Article Number 23
Number of page(s) 12
DOI https://doi.org/10.1051/bmdcn/2017070423
Published online 13 November 2017

© Author(s) 2017. This article is published with open access by China Medical University

Licence Creative Commons
Open Access This article is distributed under terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided original author(s) and source are credited.

1. Introduction

1.1. Lung Cancer

Among all forms of cancer, lung cancer is the leading cause of mortality worldwide [1, 2]. It accounts for 1.4 million (or 17.7%) of all annual cancer deaths. Lung adenocarcinoma is the most common kind of lung cancer, found in both smokers and non-smokers, as well as those under the age of 45. Adenocarcinoma accounts for about 30 percent of primary lung tumours in male smokers and 40 percent in female smokers. Among non-smokers, these percentages approach 60 percent in males and 80 percent in females. This particular kind of lung cancer is also more common among Asian populations (www.cancer.gov). A rising death rate from lung cancer has been observed in Taiwan. Between 1971 and 2001, mortality rates per 100,000 per year of age-standardized lung cancer in Taiwan increased sharply, from 12.66 to 32.93 among men and from 7.83 to 14.94 among women. To date, in Taiwan, lung cancer is the leading cause of cancer deaths among women and the second leading cause among men [3].

Despite advances in development of new treatment modalities, the overall 5-year survival rate has only slightly increased over 2.5 decades, remaining at approximately 16% [4, 5]. Early diagnostic procedures and hits, and effective screening for non-small cell lung cancer (NSCLC) is still lacking [6]. Unfortunately, many patients with lung cancer are diagnosed at a late stage (i.e. stage III b or IV), and there is no curative treatment for such an advanced stage [7]. In Taiwan, liver, lung, stomach, colon, and oral cavity cancers are the five leading cancers responsible for cancer deaths among males; while lung, liver, cervix uteri, breast, and stomach are the five leading cancers responsible for cancer deaths among females [8]. Major lifestyle variables associated with an increased cancer risk in Taiwan include habits like cigarette smoking, alcohol drinking, and betel nut chewing. Cigarette smoking has been found to increase the risk of lung, Hepatoma Cellular Carcinoma, Oral cavity, Neural progenitor cells, Esophageal, Urinary bladder, and cervical cancer in a dose–response relationship [9-12]. Similarly, in western countries tobacco smoking is also one of the main etiological factor accounting for 85% of all lung cancer cases [13]. Studies carried out on the role of one’s diet as a potential risk factor for lung cancer have provided evidence that a higher dietary intake of fruits or vegetables is correlated with a lower risk of lung cancer. As only 10-15% of (heavy) smokers develop lung cancer, endogenous factors are thought to play an important role as well. Although lung cancer rarely results from inherited mutations of oncogenes or tumour suppressor genes, it has been related to a decreased capacity to detoxify certain types of cancer-causing chemicals or tobacco carcinogens. Notably, decreased DNA repair capacity and/or increasing cellular susceptibility to the accumulation of mutations, have been found to be independent risk factors specifically for the development of NSCLC [14].

There are two main types of lung cancer: non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), and 80- 85 % of diagnoses are for non-small cell lung cancer [15]. The cancer cells of each type grow and spread via different ways. Based on histological types, NSCLC is primarily classified as squamous cell carcinoma, adenocarcinoma, or large-cell carcinoma [16]. Other less prevalentsubtypes, such as bronchioloalveolar carcinoma (BAC), comprise only 3-4% of cases, with 10-15% of adenocarcinomas having BAC features [17]. SCLC represents about 15-20% of lung cancer cases that present neuroendocrine morphological features [18].

1.2. Therapy for lung cancer

Treatment of any cancer aims to remove or destroy the cancerous cells without killing normal cells. The most common types of treatment for cancer include surgery, radiation, and chemotherapy which can be used either alone or in combination with each other or other therapies. Surgery involves removing the obvious cancerous tissue and it is the primary treatment for most cancers, particularly solid tumours. Ultrasonic and/or CD scanners are used as diagnostic tools to confirm a biochemical diagnosis and further determine the extent and spread of the tumour. Radiation therapy is the application of high energy X-rays to shrink a tumour. It is mostly used in conjunction with surgery or alternative chemotherapy or as a neo-adjuvant therapy to aid in surgery by reducing the size of a tumour and is considered local treatment since it affects only the tumour region. However, the therapeutic efficacy of radiotherapy alone for treating locally or regionally advanced cancer is often limited by tumour radio-resistance, systemic tumour progression, and local or distant metastases [19, 20]. Chemotherapy will be discussed in detail below in Section Two.

NSCLC is diagnosed at an advanced/ stage in a majority of patients for whom systemic therapy remains the basis of treatment [21, 22], even though treatment outcomes for NSCLC are still considered to be disappointing [23, 24]. Thus, NSCLC remains one of the most threatening cancers to treat. Recent advances have enabled scientists to better investigate the potential use of natural compounds for the treatment or control of various cancerous diseases. Prior to 1990, only a few cytotoxic drugs had confirmed activity against NSCLC, but a series of trials established platinum-based chemotherapy with taxanes (paclitaxel and doc-etaxel), vinca alkaloids (vinorelbine), and gemcitabine as the most effective treatment regimen [5]. But these chemotherapy-based regimens appear to have reached a therapeutic plateau; hence, effective, better-tolerated treatments are needed to overcome this issue [25].

2. Chemotherapy Drugs and treatment

Genomic studies have been promoting an effective application of anticancer drugs and many anticancer reagents in lung cancer chemotherapy treatment have progressively become ineffective for patients with a positive mutation of the tumour marker p53 [26]. Chemotherapy is the application of chemicals or drugs to kill cancer cells, and its effects are systemic. So far, there are several different classes of anticancer drugs based on their mechanisms of action, and they include the following: a) alkylating agents which damage DNA; b) anti-metabolites that replace the normal building blocks of RNA and DNA; c) antibiotics that interfere with the enzymes involved in DNA replication; d) topoisomerase inhibitors that inhibit either topoisomerase I or II, which are the enzymes involved in unwinding DNA during replication and transcription; e) mitotic inhibitors that inhibit mitosis and cell division; and f) corticosteroids, which are used for the treatment of cancer and to relieve the side effects from other drugs (Table 1).

Patients with unresectable and metastatic cancer may benefit from (palliative) chemotherapy. According to current guidelines, first-line chemotherapeutic treatment consists of a platinum agent-based doublet, e.g. cisplatin or carboplatin in combination with a third-generation cytotoxic drug, gemcitabine, a taxane (paclitaxel, docetaxel), or vinorelbine. Meta-analyses of randomized clinical trials comparing cisplatin with carboplatin suggest that the clinical outcome of cisplatin doublets is slightly superior to carboplatin-based chemotherapy without being associated with an increase in severe toxic effects [27, 28]. Another meta-analysis showed a reduction in overall mortality in gemcitabine-platinum regimens as compared to platinum-based comparator regimens [29]. In late 2006, bevacizumab, a monoclonal antibody directed against vascular endothelial growth factor (VEGF), was approved in combination with paclitaxel and carboplatin chemotherapy for first-line treatment of patients with non-squamous NSCLC [30] [31]. Several anticancer drugs applied to the treatment of lung cancer (bleomycin, doxorobucin, etoposide (VP-16), cisplatin, and methotrexate) have been reported to enhance Fas ligand (FasL) expression on the surface of Fas receptor–expressing cells, suggesting that apoptosis caused by these drugs may be mediated by means of Fas cross-linking [32, 33]. Platinum drugs are effective for patients with a positive K-ras mutation, while a number of drugs are not useful for those with increased Her-2 expression. In addition, an increased expression of p27 enhances the efficacy of taxanes [34], while taxanes are ineffective for patients with a positive mutation of beta-tubulin. In conclusion, cisplatin and other platinum drugs would not benefit patients who have a high excision repair protein (ERCC1) expression [35].

Table 1

- Current regimen of treatment for lung cancer.

2.1. Effects of Cisplatin

Cisplatin (cis-diamminedichloroplatinum, DDP) is among the most effective and widely used chemotherapeutic agents employed for treatment of solid tumours. It is a platinum-based compound that forms intra- and inter-strand adducts with DNA, and thus it is a potent inducer of cell cycle arrest and apoptosis in most cancer cell types [36]. Unfortunately, many patients with these malignancies eventually relapse and become refractory (drug resistant) to chemotherapy either intrinsically (e.g. as observed in patients with colorectal, lung, and prostate cancer) or acquired following cisplatin chemotherapy (as often seen in patients with ovarian cancer) [37, 38]. Cancer cells can develop cisplatin resistance through changes in (1) drug transport leading to reduced intracellular cisplatin accumulation, (2) an enhanced drug detoxification system due to elevated levels of intracellular scavengers such as glutathione and/or metallothioneins, (3) changes in DNA repair involving increased nucleotide excision repair, inter-strand crosslink repair or loss of mismatch repair, (4) changes in DNA damage tolerance mechanisms, and finally (5) changes in the apoptotic cell death pathways [39-42]. Cisplatin resistance might result in conjunction with GSH followed by the inactivation of cisplatin or the prevention of cisplatin-adducts formation. The level of GST-π isoenzyme expression has been found to be significantly associated with intrinsic resistance to cisplatin in lung cancer cell lines [43].

2.2. Effects of Taxanes

The chemotherapeutic agents known as taxanes have emerged as one of the most powerful classes of compounds to combat cancer, exhibiting a wide range of activity. The tubulin/microtubule complex has been proven to be a clinically useful antitumor target. The examples of chemotherapeutics that act via perturbation of tubulin polymerization include paclitaxel (Taxol®), docetaxel (Taxotere®), vinblastine, and discodermolide. First, docetaxel is a semi-synthetic derivative of paclitaxel. Next, vinblastine, unlike the other three compounds that all stabilize microtubules, aggregates tubulin and leads to microtubule depolymerisation [43-46].

Randomized clinical trials evaluating docetaxel and paclitaxel in a first-line treatment setting for metastatic breast, lung, ovarian, and digestive cancers, as well as in the adjuvant setting for breast cancer, have confirmed that taxanes are leading contributors to the armamentarium of cancer treatments [47]. Though the taxanes share similar mechanisms of action, differences are apparent in their molecular pharmacology, pharmacokinetics, and pharmacodynamic profiles. These differences may account for the differences observed between the taxanes in their clinical activity and toxicity (Fig. 1).

thumbnail Fig. 1

Chemical structures of anti-tumour agents with clinical applications.

Paclitaxel

Paclitaxel is used as a first-line chemotherapy treatment for NSCLC, but patients' acquired resistance becomes a critical problem. Tubulin is the “building block” of microtubules, and agents that bind to tubulin are believed to block cell division by interfering with the function of the mitotic spindle, blocking the cells at the metaphase-anaphase junction of mitosis. Microtubules are complex structures involved in numerous cellular functions, including the maintenance of cell shape, intracellular transport, secretion, and neurotransmission. Moreover, microtubules are highly dynamic and unstable structures that are constantly incorporating free dimers and releasing dimers into the soluble tubulin pool [47]. Chang et al. (1993) and Murphy et al. (1993) have evaluated a 24-h infusion schedule (regimen) of paclitaxel in the treatment of advanced and metastatic NSCLC and yielded response rates of 21% and 24% respectively [48, 49], while short infusion schedules for 3 h and 1 h yielded similar results [50, 51]. Docetaxel exhibits greater affinity to ß-tubulin, targeting centrosome organization and acting on cells during three phases of the cell cycle (S/G2/M), whereas paclitaxel causes cell dam age by affecting the mitotic spindle in the G2 and M phases of the cell cycle, and maximum resistance to paclitaxel is early in the S phase [52, 53]. Recently a report has shown that concentrations of paclitaxel >10 nM inhibit endothelial cell proliferation through a G2-M arrest and induce subsequent cell death by apoptosis, similar to the effects it has on tumour cell lines [54]. During the last decade, additional activities of taxol have been described in many aspects including taxol-induced phosphorylation of I-κBα, while several studies have also shown that taxol can directly activate survival pathways such as Bcl-2, Akt, Cox-2, mitogenactivated protein kinase, etc., independent of NF-κB [55, 56].

The phosphorylation of Bcl-2 appears to be a hallmark of cell death induced by paclitaxel, but the correlation between this event, mitotic arrest, and apoptosis remains controversial. Initial reports have suggested that the phosphorylation of Bcl-2 leads to inactivation of its antiapoptotic function [57]. Currently, the molecular mechanism by which paclitaxel-induced mitotic arrest leads to apoptosis is not clear, although evidence for the involvement of several signalling pathways has been shown including the action of various protein kinases such as mitogen-activated protein kinases (MAPK), serine/threonine kinase-dependent phosphorylation of Bcl-2, and the p53 pathway [58]. Activation of the caspase-9/Apaf-1/cytochrome c apoptosome in the mitochondrialdependent apoptotic pathway leads in turn to caspase-3 activation [59]. Ofir et al. (2002) have also found that procaspase-9 is not activated after taxol treatment in MCF-7 breast cancer and SKOV3 ovarian cancer cell lines, and this drug induces apoptosis independently of caspases-3 and -9 [60]. However, during taxol-induced apoptosis in CCRF-HSB-2 cells (Human Caucasian acute lymphoblastic leukaemia), caspase-3 is activated but independently of caspase-9. It appears that the effect of taxol on caspase-9 activation is also cell type-specific; for instance, taxolinduced apoptosis in the human leukemia HL-60 cell line has been observed to trigger the release of cytochrome c into the cytosol and induce Apaf-1-mediated caspase-3 and -9 activities [61, 62]. Park et al. (2004) and Lin et al. (2000) have demonstrated taxol-induced apoptosis through an ROS-independent pathway in human lymphoblastic leukemia cells and in hepatoma cells [63, 64].

Resistance to paclitaxel is defined as disease progression during treatment, failure to achieve tumour regression after a minimum of four courses of therapy, or recurrence of disease within 6 months of completion of paclitaxel therapy. The radio-sensitizing effects of docetaxel relative to paclitaxel have been evaluated in an in vitro comparative analysis using three human cancer cell lines (cervical cancer, mesothelioma, and lung cancer). Results showed that all three cell lines are more sensitive to docetaxel than to paclitaxel and that, although mesothelioma cells were intrinsically resistant to both radiation and taxanes, the resistance is partially overcome with administration of docetaxel before radiation [65-67]. Nevertheless, most patients with advanced lung cancer develop resistance to Taxol. In another study it was proven that paclitaxel, when combined with apoptin, can specifically inhibit expression resulting in additive cytotoxic activity in osteosarcoma and NSCLC cells [68]. A major impediment to paclitaxel cytotoxicity in NSCLC is the establishment of multi-drug resistance. In response to this, paclitaxel has been combined with other chemotherapeutic agents, resulting in increased response rates from 35 to > 50% [69, 70].

The involvement of caspases in taxane-induced cell death is cell line-dependent. Inhibition of caspase 1 and caspase 3 in a mouse cell line has been observed to prevent docetaxel-induced DNA fragmentation [71]. However, a pan caspase inhibitor failed to abolish decreases in cell viability by docetaxel in gastric cancer cells [72]. Moreover, taxanes have been found to cause apoptosis in caspase 3-deficient MCF-7 breast cancer cells [73]. Paclitaxel also activates caspase 8 in human colon cancer cells, suggesting a potential interaction between intrinsic and extrinsic apoptotic pathways [72].

2.3. Effects of Gefitinib

Gefitinib is an oral agent that is used in targeting the epidermal growth factor receptor tyrosine kinase, and it has a certain efficacy against non-small cell lung cancer [74]. EGFR-TKIs, gefitinib-IRESSA has been shown to inhibit cell proliferation which overexpresses EGFR, including some ER-negative cell lines [75, 76]. In Phase I trials, oral gefitinib tumour recession was observed in a variety of cancer types [77]. In Phase II studies, 500 mg/day of oral gefitinib used to treat breast cancer and 250 and 500 mg/day in NSCLC showed similar tolerability; however, in the case of NSCLC better tolerability was found in the lower dosage [78-80]. Gefitinib decreased tumour thyroid cancer cell growth in vitro and in vivo that overexpresses EGFR [81]. Since 2003, the FDA has approved three generations of EGFR tyrosine kinase inhibitor (TKI) including gefitinib, erlotinib, afatinib, and osimertinib [82, 83]. Gefitinib is a specific EGFR-TKI that is extensively applied to the treatment of non-small lung cells in clinical practice [84]. Gefitinib as a choice for first-line therapy significantly improved NSCLC patients' survival rate with EGFR mutation [85, 86]. Nonetheless, acquired resistance after gefitinib therapy is almost unavoidable and limits therapeutic success rate. To overcome resistance to EGFR-TKIs, a combination of them with other compounds has to be designed [87].

2.4. Effects of Gemcitabine

Gemcitabine in vitro and phase I studies has shown activity against many kinds of tumours, especially NSCLC [88-90]. However, this drug is highly cytotoxic and development of innate or acquired drug resistance has been a major challenge in gemcitabine therapy and has led to a reduction in the survival rate of cancer patients [91-93]. It is being used in combination with other drugs for the treatment of locally advanced or metastatic non-small-cell lung cancer, bladder cancer, and ovarian cancer [94]. Gemcitabine treatment showed greater inhibitory activity against breast cancer cells [95, 96]. In prostate cancer cells, a combination of gemcitabine with compounds αM and γM showed synergistic anti-cancer effects [97]. A combination of gemcitabine with other capecitabines such as cisplatin [98, 99], fluorouracil [100] and erlotinib[100], and more on stage III pancreatic cancer patients showed a slight synergistic effect. Therefore, development of the use of natural compounds to enhance gemcitabine in treating cancer is urgently needed.

2.5. Effects of Erlotinib

Erlotinib, like gefitinib, is a small molecular agent that is used to target epidermal growth factor receptors (EGFRs), and the inhibition of EGFR has become a main target for treating advanced non-small cell lung cancer (NSCLC) [101]. However, it is expensive and its efficacy is limited by primary or secondary drug resistance, which develops over extended periods of treatments [102]. Combined miR-34a and EGFR-TKIs synergistically sensitize both EGFR wild-type and mutant NSCLC cells [103].

3. Radiotherapy/chemoradiotherapy

Approximately one out of every three patients with NSCLC has a locally advanced tumor that is surgically unresectable [104]. Hence, radiotherapy remains a major therapeutic option for patients with such advanced lung cancer. Nevertheless, the effects of irradiation on malignant biological behaviours (e.g. migration and transformation of cancer cells) have yet to be fully clarified. However, we know that the median overall survival rate with radiotherapy alone is 9 to 11 months, and the 5-year survival rate is disappointingly low, at 3% to 10% [105-108]. Although radiotherapy is a major therapeutic modality for cancer treatment, previous findings have suggested that radiation promotes tumour migration, distant metastasis, and the invasive potential of cancer cells in disadvantage [109-111]. In contrast to SCLC cell lines, NSCLC cell lines are generally less sensitive to radiation and are poorly affected by current therapies, which means surgery represents almost the only curative therapy for about 25% of patients who are resectable at diagnosis [112].

On the other hand, pre-treatment with chemotherapy causes cancer cells to become sensitive to radiation therapy. Consequently, several studies have investigated the effects of combining radiotherapy with chemotherapy for patients with unresectable stage IIINSCLC [113]. Sause et al. (1995) have found similar results using a sequential approach, with a median overall survival rate of 13.8 months [114]. Zhang et al. (2010) have shown that wortmanin acts as a powerful radiosensitizer in NSCLC cells by inhibiting PI3K/Akt survival signalling and DNA-PKCs [115]. Similarly, gefitinib radiosensitizes NSCLC cells by inhibiting ataxi telangiectasia mutated (ATM) activity and thereby inducing mitotic cell death, and that COX-2 overexpression in NSCLC cells inhibits this action of gefitinib [116]. In addition, Schaake-Koning and colleagues administered cisplatin concurrently with radiotherapy to patients with nonmetastatic but inoperable NSCLC and demonstrated improved rates of survival and control of local disease as compared with radiotherapy alone [113]. However, this study reported increased toxicity, nausea, and vomiting in the concurrent chemoradiotherapy group. Therefore, it may be helpful in terms of lowering toxicity and enhancing the effect of radiation therapy if we can administer radiation therapy and natural compounds that can sensitize NSCLC for radiation therapy. Thus, searching for an effective sensitizer is becoming a hots topic and natural compounds including herbs and marine life are attractive and potentially viable alternatives to researchers.

4. Natural compounds

Natural compounds have long been a source of anticancer compounds. For many years, traditional Chinese medicines (TCM) have been applied for the treatment of cancers in China and beyond [117]. Herbal medicines are generally low in cost, plentiful, and show very little toxicity or side effects in clinical practice. Some of the most valuable compounds (such as paclitaxel and the Vinca alkaloids) were discovered either serendipitously or from slow and laborious in vivo screening [118]. Much of the current research in cancer therapeutics is aimed at developing drugs or vaccines to target key molecules that can inhibit tumour cell growth, metastasis, and proliferation. The cancer preventive and/ or protective activities of natural compounds lie in their effects on cellular defences like detoxifying and antioxidant enzyme systems, and the induction of anti-inflammatory and antitumor or anti-metastasis responses, often by targeting specific key transcription factors [119].

In clinical treatment, most NSCLC patients respond poorly to conventional chemotherapy because of the emergence of resistance. Hence, there is an urgent need to develop novel treatment strategies to improve the sensitivity of cancer cells to chemotherapy-induced cell death. Below we present some examples of how apoptosis pathways are targeted by select naturally occurring agents and how these events can be exploited for cancer therapy.

4.1. Wortmannin and Roscovitine

The purine analogues roscovitine is a small molecule that inhibits the activity of cyclin-dependent kinases (CDKs) via direct competition in the ATP-binding site. It is particularly active against Cdk1 (Cdc2), Cdk2, and Cdk5 and induces G1 and G2-M cell cycle arrest [120]. Roscovitine has been reported to have antitumour effects in different cancer cell lines [121-123]. Similarly, roscovitine induces apoptosis in A549 cells in a dose-dependent manner. Meanwhile, wortmannin, a fungal metabolite, is a potent specific PI3K inhibitor, which binds to the p110 catalytic subunit of PI3K and irreversibly inhibits the enzyme [124], something which could chemosensitize three human tumour cell lines (A549, HCT116 and HeLa cells). In A549 cells, wortmannin increases roscovitine-induced apoptosis in a dose-dependent manner, which is correlated with the inhibition of phosphorylated PKB/Akt level. Wortmannin enhances the effects of roscovitine by causing a pronounced reduction of mitochondrial membrane potential (MMP) and increases of cytochrome c release and active caspase-3, as well as enhances the activation of Bax and Bad, including Bax oligomerization and the mitochondrial translocation of Bax and Bad. Taken together, these results provide evidence for the potential application of a roscovitine and wormannin combination in clinical treatment for solid tumours [125].

4.2. Cordyceps militaris

Cordyceps militaris is well known as a traditional medicinal mushroom and is a potentially interesting candidate for use in cancer treatment. Water extract of C. militaris (WECM) induces the apoptosis of A549 cells through a signalling cascade of death receptor-mediated extrinsic and mitochondria-mediated intrinsic caspase pathways. It has also been concluded that apoptotic events due to WECM are mediated with diminished telomerase activity through the inhibition of hTERT transcriptional activity [126].

4.3. Resveratrol

Resveratrol has been assessed in over 110 clinical trials, such as in DM and metabolic syndrome patients and certain types of cancer patients [127]. Resveratrol (3,5,4'-trihydroxy-stilbene) is a phytoalexin found in red wine and a variety of plants, including grapes, peanuts, mulberries, and legumes and are produced due to stress, injury, fungal infection, or UV exposure [128, 129]. Resveratrol induces antioxidant and anti-inflammatory effects and also has been found to inhibit the proliferation of a various cancer cells [130, 131]. What’s more, resveratrol has been found to inhibit platelet aggregation [132] and also to have antioxidant properties [133]. Resveratrol is reported to have protective effects against lung cancer; it alters a large number of genes and proteins and inhibits A549 cell proliferation by inducing cell cycle arrest, inducing apoptosis, and by altering the intracellular Smad signalling of the TGF-β pathway [134]. Resveratrol has already been established as an antiproliferative agent in A549 human lung cancer cells, and this effect has been correlated with the suppression of the phosphorylation of Rb protein and transcription factors such as nuclear factor-kB (NF-kB) and activator protein-1 [135]. It has been identified that resveratrol administration in colorectal adenocarcinoma patients reduces tumour cell proliferation [136].

4.4. OSU03013

OSU03013 is a derivative of celecoxib. Although celecoxib is an inhibitor of cyclooxygenase (COX)-2, substantial data indicate that celecoxib-induced apoptosis cell death occurs through a COX-2–independent pathway [137]. A recent study indicated that OSU03013 can induce apoptosis in prostate cancer cells through the 3-phosphoinositide–dependent kinase 1 (PDK1)/AKT signalling pathway and may more strongly inhibit cell growth than celecoxib [138]. In addition, OSU03013 has been used in breast cancer treatment, and it has been found to have a higher cytotoxicity especially in breast cancer cells with epidermal growth factor receptor (HER)-2 overexpression [139]. Tong et al. (2006) have found that 10 μM of OSU03013 can induce cytochrome C-mediated apoptosis in A549 lung cancer cells especially at low concentrations of exogenous-expressed AKT [140]. Similarly, Tan et al. (2008) found that OSU03013 can affect several pathways such as the cAMP-dependent protein kinase (PKA) and Wnt/h catenin pathways and cause ER stress–induced apoptosis at a dose as low as 2 μM in lung cancer cells [141].

4.5. Myricetin

Myricetin, a flavonoid commonly found in tea, wines, berries, fruits, and medicinal plants, has been reported to possess antioxidative, antiproliferative, and anti-inflammatory qualities. Previous studies have shown that myricetin exerts an antiproliferative effect on lung, esophageal, leukemia, and prostate cancer cells [142-144]. Myricetin may act as a direct antioxidant that scavenges or quenches oxygen free radicals, and as an indirect antioxidant that induces antioxidant enzymes to protect cells against H2O2-induced cell damage [145].

4.6. Berberine

Berberine is an isoquinoline derivative alkaloid isolated from many medicinal herbs, such as Hydrastis canadensis, Cortex phellodendri, and Rhizoma coptidis. It is widely used in Traditional Chinese medicine for the treatment of inflammatory diseases and anti-microbial activities [146-149]. Berberine has been reported to have a wide range of pharmacological effects, including interaction with DNA to form complexes, inhibition of DNA and protein synthesis, an arresting effect on cell cycle progress, an inhibition of tumour cell proliferation, and an anticancer effect. It has been reported that berberine decreases the motility and invasion of non-small lung cancer cells by alleviating the activation of c-Fos, c-Jun, and NF-κB, and thus inhibits uPA, MMP2 proteins [150]. Berberine exerts an antitumor effect via inhibition of cell proliferation and induction of apoptosis in ovarian cancer cells[151]. Cotreatment of Curcumin and Berberine has displayed synergistic chemopreventive effects via inducing caspase-dependent apoptosis and autophagic cell death through ERK and JNK/Beclin1/Bcl-2 signalling pathways, respectively, in breast cancer cell lines [152].

4.7. Antroquinonol

Antroquinonol, a ubiquinone derivative isolated from mycelia and the fruiting bodies of A. camphorata has been reported to exhibit cytotoxic activities against cancer cell lines MCF-7, MDA-MB-231, Hep 3B, Hep G2 and DU-145, LNCaP with the IC50 values ranging from 0.13 to 6.09 μM [153]. Along with other groups, we have have found that antroquinonol inhibits lung cancer and liver cancer cells by modulating the AMP-activated protein kinase (AMPK) or phosphatidylinositol-3-kinase (PI3K)/ mammalian target of rapamycin (mTOR) pathways [154, 155]. Recent studies have reported that Antroquinonol induces apoptosis and autophagy of pancreatic cancer cells [156]. In colon cancer, ANQ has been found to suppress stem cell-like properties by targeting PI3K/AKT/β-catenin signalling [157].

5. Conclusion

Surgery or radiotherapy is the standard option for patients with early stages of NSCLC. Chemotherapy has shown some benefit when used alone in patients with stage IV of the disease, as well as in combination with radiotherapy in patients with locally advanced disease and in the preoperative setting in those with early stages of NSCLC. Platinum drugs are still considered of crucial interest based on clinical studies and the results of meta-analyses, with their inconvenience being their observed toxicity and the inherent resistance. The poor efficacy and considerable toxicity of chemotherapy has caused great pessimism for many years regarding this approach, as only a small positive impact on survival rates was observed. Chemotherapy is now a broadly accepted form of therapy for stage IIIB/IV NSCLC, and there is growing interest in its use in earlier stages of the disease when combined with other (local) therapy. Meanwhile, natural compounds have been used to treat various diseases and are becoming a significant research area for drug discovery. Using natural agents along with chemotherapy drugs in patients with advanced and/or refractory solid tumours could reduce the toxicity risk produced by chemotherapy, and this could be an accessible approach to cancer control and management.

Conflicts of Interest

The authors wish to declare they have no conflicts of interest.

References

  1. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin 2005; 55: 74-108. [CrossRef] [PubMed] [Google Scholar]
  2. Pisani P, Parkin DM, Bray F, Ferlay J. Estimates of the worldwide mortality from 25 cancers in 1990. Int J Cancer. 1999; 83: 18-29. [CrossRef] [PubMed] [Google Scholar]
  3. Liaw YP, Huang YC, Lien GW. Patterns of lung cancer mortality in 23 countries: application of the age-period-cohort model. BMC Public Health. 2005; 5: 22. [CrossRef] [Google Scholar]
  4. Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ. Cancer statistics, 2007. CA Cancer J Clin. 2007; 57: 43-66. [CrossRef] [PubMed] [Google Scholar]
  5. Spira A,Ettinger DS. Multidisciplinary management of lung cancer. N Engl J Med. 2004; 350: 379-92. [CrossRef] [PubMed] [Google Scholar]
  6. Herbst RS, Bunn PA, Jr. Targeting the epidermal growth factor receptor in non-small cell lung cancer. Clin Cancer Res. 2003; 9: 5813-24. [PubMed] [Google Scholar]
  7. Broker LE, Glaccone G. The role of new agents in the treatment of non-small cell lung cancer. Eur J Cancer. 2002; 38: 2347-61. [CrossRef] [PubMed] [Google Scholar]
  8. Chen CJ, You SL, Lin LH, Hsu WL, Yang YW. Cancer epidemiology and control in Taiwan: a brief review. Jpn J Clin Oncol. 2002;32 Suppl: S66-81. [Google Scholar]
  9. Chen CJ, Liang KY, Chang AS, Chang YC, Lu SN, Liaw YF, et al. Effects of hepatitis B virus, alcohol drinking, cigarette smoking and familial tendency on hepatocellular carcinoma. Hepatology. 1991; 13: 398-406. [CrossRef] [PubMed] [Google Scholar]
  10. Lin TM, Yang CS, Tu SM, Chen CJ, Kuo KC, Hirayama T. Interaction of factors associated with cancer of the nasopharynx. Cancer. 1979; 44: 1419-23. [CrossRef] [PubMed] [Google Scholar]
  11. Hung HC, Chuang J, Chien YC, Chern HD, Chiang CP, Kuo YS, et al. Genetic polymorphisms of CYP2E1, GSTM1, and GSTT1; environmental factors and risk of oral cancer. Cancer Epidemiol Biomarkers Prev. 1997; 6: 901-5. [PubMed] [Google Scholar]
  12. Liaw KM, Chen CJ. Mortality attributable to cigarette smoking in Taiwan: a 12-year follow-up study. Tob Control. 1998;7: 141-8. [CrossRef] [PubMed] [Google Scholar]
  13. Peto R, Darby S, Deo H, Silcocks P, Whitley E, Doll R. Smoking, smoking cessation, and lung cancer in the UK since 1950: combination of national statistics with two case-control studies. BMJ. 2000; 321: 323-9. [CrossRef] [PubMed] [Google Scholar]
  14. Wei Q, Cheng L, Amos CI, Wang LE, Guo Z, Hong WK, et al. Repair of tobacco carcinogen-induced DNA adducts and lung cancer risk: a molecular epidemiologic study. J Natl Cancer Inst. 2000; 92: 1764-72. [CrossRef] [PubMed] [Google Scholar]
  15. Ettinger DS. Overview and state of the art in the management of lung cancer. Oncology (Williston Park) 2004; 18: 3-9. [Google Scholar]
  16. Brambilla E, Travis WD, Colby TV, Corrin B, Shimosato Y. The new World Health Organization classification of lung tumours. Eur Respir J. 2001; 18: 1059-68. [CrossRef] [PubMed] [Google Scholar]
  17. Read WL, Page NC, Tierney RM, Piccirillo JF, Govindan R. The epidemiology of bronchioloalveolar carcinoma over the past two decades: analysis of the SEER database. Lung Cancer. 2004; 45: 137-42. [CrossRef] [PubMed] [Google Scholar]
  18. Beasley MB, Brambilla E, Travis WD. The 2004 World Health Organization classification of lung tumors. Semin Roentgenol. 2005; 40: 90-7. [CrossRef] [PubMed] [Google Scholar]
  19. Shinoura N, Yamada R, Okamoto K, Nakamura O, Shitara N. Local recurrence of metastatic brain tumor after stereotactic radiosur-gery or surgery plus radiation. J Neurooncol. 2002; 60: 71-7. [CrossRef] [PubMed] [Google Scholar]
  20. Lavine SD, Petrovich Z, Cohen-Gadol AA, Masri LS, Morton DL, O'Day SJ, et al. Gamma knife radiosurgery for metastatic melanoma: an analysis of survival, outcome, and complications. Neurosurgery. 1999; 44: 59-64; discussion 64-6. [CrossRef] [PubMed] [Google Scholar]
  21. Winton T, Livingston R, Johnson D, Rigas J, Johnston M, Butts C, et al. Vinorelbine plus cisplatin vs. observation in resected non-small-cell lung cancer. N Engl J Med. 2005; 352: 2589-97. [CrossRef] [PubMed] [Google Scholar]
  22. Arriagada R, Bergman B, Dunant A, Le Chevalier T, Pignon JP, Vansteenkiste J. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med. 2004; 350: 351-60. [CrossRef] [PubMed] [Google Scholar]
  23. Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med. 2002; 346: 92-8. [CrossRef] [PubMed] [Google Scholar]
  24. Hanna N, Shepherd FA, Fossella FV, Pereira JR, De Marinis F, von Pawel J, et al. Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol. 2004; 22: 1589-97. [CrossRef] [PubMed] [Google Scholar]
  25. Mahalingam D, Mita A, Mita MM, Nawrocki ST, Giles FJ. Targeted therapy for advanced non-small cell lung cancers: historical perspective, current practices, and future development. Curr Probl Cancer. 2009; 33: 73-111. [CrossRef] [PubMed] [Google Scholar]
  26. Lowe SW, Bodis S, McClatchey A, Remington L, Ruley HE, Fisher DE, et al. p53 status and the efficacy of cancer therapy in vivo. Science 1994; 266: 807-10. [CrossRef] [PubMed] [Google Scholar]
  27. Hotta K, Matsuo K, Ueoka H, Kiura K, Tabata M, Tanimoto M. Meta-analysis of randomized clinical trials comparing Cisplatin to Carboplatin in patients with advanced non-small-cell lung cancer. J Clin Oncol. 2004; 22: 3852-9. [CrossRef] [PubMed] [Google Scholar]
  28. Ardizzoni A, Boni L, Tiseo M, Fossella FV, Schiller JH, Paesmans M, et al. Cisplatin-versus carboplatin-based chemotherapy in first-line treatment of advanced non-small-cell lung cancer: an individual patient data meta-analysis. J Natl Cancer Inst. 2007; 99: 847-57. [CrossRef] [PubMed] [Google Scholar]
  29. Le Chevalier T, Scagliotti G, Natale R, Danson S, Rosell R, Stahel R, et al. Efficacy of gemcitabine plus platinum chemotherapy compared with other platinum containing regimens in advanced non-small-cell lung cancer: a meta-analysis of survival outcomes. Lung Cancer. 2005; 47: 69-80. [CrossRef] [PubMed] [Google Scholar]
  30. Cohen MH, Gootenberg J, Keegan P, Pazdur R. FDA drug approval summary: bevacizumab (Avastin) plus Carboplatin and Paclitaxel as first-line treatment of advanced/metastatic recurrent nonsquamous non-small cell lung cancer. Oncologist. 2007; 12: 713-8. [CrossRef] [PubMed] [Google Scholar]
  31. Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006; 355: 2542-50. [CrossRef] [PubMed] [Google Scholar]
  32. Muller M, Strand S, Hug H, Heinemann EM, Walczak H, Hofmann WJ, et al. Drug-induced apoptosis in hepatoma cells is mediated by the CD95 (ApO-1/Fas) receptor/ligand system and involves activation of wild-type p53. J Clin Invest. 1997; 99: 403-13. [CrossRef] [PubMed] [Google Scholar]
  33. Fulda S, Friesen C, Debatin KM. Molecular determinants of apoptosis induced by cytotoxic drugs. Klinische Padiatrie. 1998; 210: 148-52. [CrossRef] [PubMed] [Google Scholar]
  34. Cho JY, Kim JH, Lee YH, Chung KY, Kim SK, Gong SJ, et al. Correlation between K-ras gene mutation and prognosis of patients with nonsmall cell lung carcinoma. Cancer. 1997; 79: 462-67. [CrossRef] [PubMed] [Google Scholar]
  35. Britten RA, Liu D, Tessier A, Hutchison MJ, Murray D. ERCC1 expression as a molecular marker of cisplatin resistance in human cervical tumor cells. Int J Cancer. 2000; 89: 453-57. [CrossRef] [PubMed] [Google Scholar]
  36. Cohen SM, Lippard SJ. Cisplatin: from DNA damage to cancer chemotherapy. Prog Nucleic Acid Res Mol Biol. 2001; 67: 93-130. [CrossRef] [PubMed] [Google Scholar]
  37. Kartalou M, Essigmann JM. Mechanisms of resistance to cisplatin. Mutat Res. 2001; 478: 23-43. [CrossRef] [PubMed] [Google Scholar]
  38. Rabik CA, Dolan ME. Molecular mechanisms of resistance and toxicity associated with platinating agents. Cancer Treat Rev. 2007; 33: 9-23. [CrossRef] [PubMed] [Google Scholar]
  39. Perez RP. Cellular and molecular determinants of cisplatin resistance. Eur J Cancer. 1998; 34: 1535-42. [CrossRef] [PubMed] [Google Scholar]
  40. Niedner H, Christen R, Lin X, Kondo A, Howell SB. Identification of genes that mediate sensitivity to cisplatin. Molecular Pharmacology. 2001; 60: 1153-60. [CrossRef] [PubMed] [Google Scholar]
  41. Mansouri A, Ridgway LD, Korapati AL, Zhang Q, Tian L, Wang Y, et al. Sustained activation of JNK/p38 MAPK pathways in response to cisplatin leads to Fas ligand induction and cell death in ovarian carcinoma cells. J Biol Chem. 2003; 278: 19245-56. [CrossRef] [PubMed] [Google Scholar]
  42. Seve P, Dumontet C. Chemoresistance in non-small cell lung cancer. Curr Med Chem Anticancer Agents. 2005; 5: 73-88. [CrossRef] [PubMed] [Google Scholar]
  43. Rowinsky EK, Onetto N, Canetta RM, Arbuck SG. Taxol: the first of the taxanes, an important new class of antitumor agents. Semin Oncol. 1992; 19: 646-62. [PubMed] [Google Scholar]
  44. Eckardt JR. Antitumor activity of docetaxel. Am J Health Syst Pharm. 1997; 54: S2-6. [PubMed] [Google Scholar]
  45. Neuss N, Mallett GE, Brannon DR, Mabe JA, Horton HR, Huck-step LL. Vinca alkaloids XXXIII [1]. Microbiological conversions of vincaleukoblastine (VLB, vinblastine), an antitumor alkaloid from Vinca rosea. Linn. Helv Chim Acta. 1974; 57: 1886-90. [CrossRef] [Google Scholar]
  46. TerHaar E, Kowalski RJ, Hamel E, Lin CM, Longley RE, Gunasek-era SP, et al. Discodermolide, a cytotoxic marine agent that stabilizes microtubules more potently than taxol. Biochemistry. 1996; 35: 243-50. [CrossRef] [PubMed] [Google Scholar]
  47. Gligorov J, Lotz JP. Preclinical pharmacology of the taxanes: Implications of the differences. Oncologist. 2004; 9: 3-8. [CrossRef] [EDP Sciences] [Google Scholar]
  48. Chang AY, Kim K, Glick J, Anderson T, Karp D, Johnson D. Phase II study of taxol, merbarone, and piroxantrone in stage IV non-small-cell lung cancer: The Eastern Cooperative Oncology Group Results. J Natl Cancer Inst. 1993; 85: 388-94. [CrossRef] [PubMed] [Google Scholar]
  49. Murphy WK, Fossella FV, Winn RJ, Shin DM, Hynes HE, Gross HM, et al. Phase II study of taxol in patients with untreated advanced non-small-cell lung cancer. J Natl Cancer Inst. 1993; 85: 384-8. [CrossRef] [PubMed] [Google Scholar]
  50. Gatzemeier U, Heckmayer M, Neuhauss R, Schluter I, von Pawel J, Wagner H, et al. Chemotherapy of advanced inoperable non-small cell lung cancer with paclitaxel: a phase II trial. Semin Oncol. 1995; 22: 24-8. [Google Scholar]
  51. Millward MJ, Bishop JF, Friedlander M, Levi JA, Goldstein D, Olver IN, et al. Phase II trial of a 3-hour infusion of paclitaxel in previously untreated patients with advanced non-small-cell lung cancer. J Clin Oncol. 1996; 14: 142-8. [CrossRef] [PubMed] [Google Scholar]
  52. Haldar S, Basu A, Croce CM. Bcl2 is the guardian of microtubule integrity. Cancer Res. 1997; 57: 229-33. [Google Scholar]
  53. Hennequin C, Giocanti N, Favaudon V. S-phase specificity of cell killing by docetaxel (Taxotere) in synchronised HeLa cells. Br J Cancer. 1995; 71: 1194-8. [CrossRef] [PubMed] [Google Scholar]
  54. Pasquier E, Carre M, Pourroy B, Camoin L, Rebai O, Briand C, et al. Antiangiogenic activity of paclitaxel is associated with its cyto-static effect, mediated by the initiation but not completion of a mi-tochondrial apoptotic signaling pathway. Mol Cancer Ther. 2004; 3: 1301-10. [PubMed] [Google Scholar]
  55. Bava SV, Puliappadamba VT, Deepti A, Nair A, Karunagaran D, Anto RJ. Sensitization of taxol-induced apoptosis by curcumin involves down-regulation of nuclear factor-kappaB and the serine/ threonine kinase Akt and is independent of tubulin polymerization. J Biol Chem. 2005; 280: 6301-8. [CrossRef] [PubMed] [Google Scholar]
  56. Subbaramaiah K, Hart JC, Norton L, Dannenberg AJ. Microtubule-interfering agents stimulate the transcription of cyclooxygenase-2. Evidence for involvement of ERK1/2 AND p38 mitogen-activated protein kinase pathways. J Biol Chem. 2000; 275: 14838-45. [CrossRef] [PubMed] [Google Scholar]
  57. Wang TH, Wang HS, Soong YK. Paclitaxel-induced cell death: where the cell cycle and apoptosis come together. Cancer. 2000; 88: 2619-28. [CrossRef] [PubMed] [Google Scholar]
  58. Wang LG, Liu XM, Kreis W, Budman DR. The effect of antimi-crotubule agents on signal transduction pathways of apoptosis: a review. Cancer Chemother Pharmacol. 1999; 44: 355-61. [CrossRef] [PubMed] [Google Scholar]
  59. Li H, Zhu H, Xu CJ, Yuan J. Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell. 1998; 94: 491-501. [CrossRef] [PubMed] [Google Scholar]
  60. Ofir R, Seidman R, Rabinski T, Krup M, Yavelsky V, Weinstein Y, et al. Taxol-induced apoptosis in human SKOV3 ovarian and MCF7 breast carcinoma cells is caspase-3 and caspase-9 independent. Cell Death Differ. 2002; 9: 636-42. [CrossRef] [PubMed] [Google Scholar]
  61. Ibrado AM, Liu L, Bhalla K. Bcl-xL overexpression inhibits progression of molecular events leading to paclitaxel-induced apop-tosis of human acute myeloid leukemia HL-60 cells. Cancer Res. 1997; 57: 1109-15. [Google Scholar]
  62. Perkins C, Kim CN, Fang G, Bhalla KN. Arsenic induces apop-tosis of multidrug-resistant human myeloid leukemia cells that express Bcr-Abl or overexpress MDR, MRP, Bcl-2, or Bcl-x(L). Blood. 2000; 95: 1014-22. [Google Scholar]
  63. Park SJ, Wu CH, Gordon JD, Zhong X, Emami A, Safa AR. Taxol induces caspase-10-dependent apoptosis. J Biol Chem. 2004; 279: 51057-67. [CrossRef] [PubMed] [Google Scholar]
  64. Lin HL, Liu TY, Chau GY, Lui WY, Chi CW. Comparison of 2-methoxyestradiol-induced, docetaxel-induced, and paclitaxel-induced apoptosis in hepatoma cells and its correlation with reactive oxygen species. Cancer. 2000; 89: 983-94. [CrossRef] [PubMed] [Google Scholar]
  65. Mason KA, Hunter NR, Milas M, Abbruzzese JL, Milas L. Do-cetaxel enhances tumor radioresponse in vivo. Clin Cancer Res. 1997; 3: 2431-8. [PubMed] [Google Scholar]
  66. Milas L, Milas MM, Mason KA. Combination of taxanes with radiation: preclinical studies. Semin Radiat Oncol. 1999; 9: 12-26. [PubMed] [Google Scholar]
  67. Mason K, Staab A, Hunter N, McBride W, Petersen S, Terry N, et al. Enhancement of tumor radioresponse by docetaxel: Involvement of immune system. Int J Oncol. 2001; 18: 599-606. [PubMed] [Google Scholar]
  68. Olijslagers SJ, Zhang YH, Backendorf C, Noteborn MH. Additive cytotoxic effect of apoptin and chemotherapeutic agents paclitaxel and etoposide on human tumour cells. Basic Clin Pharmacol Toxicol. 2007; 100: 127-31. [PubMed] [Google Scholar]
  69. Juretic A, Sobat H, Samija M. Combined modality therapy of non-small cell lung cancers. Ann Oncol. 1999; 10 Suppl 6: 93-8. [CrossRef] [PubMed] [Google Scholar]
  70. Belani CP. Paclitaxel and docetaxel combinations in non-small cell lung cancer. Chest. 2000; 117:144S-51S. [CrossRef] [PubMed] [Google Scholar]
  71. Suzuki A, Kawabata T, Kato M. Necessity of interleukin-1beta converting enzyme cascade in taxotere-initiated death signaling. Eur J Pharmacol. 1998; 343: 87-92. [CrossRef] [PubMed] [Google Scholar]
  72. Ganansia-Leymarie V, Bischoff P, Bergerat JP, Holl V. Signal transduction pathways of taxanes-induced apoptosis. Curr Med Chem Anticancer Agents. 2003; 3: 291-306. [CrossRef] [PubMed] [Google Scholar]
  73. Kottke TJ, Blajeski AL, Meng XW, Svingen PA, Ruchaud S, Mesner PW Jr., et al. Lack of correlation between caspase activation and caspase activity assays in paclitaxel-treated MCF-7 breast cancer cells. J Biol Chem. 2002; 277: 804-15. [CrossRef] [PubMed] [Google Scholar]
  74. Lee SJ, Lee HS, Choi JS, Na JO, Seo KH, Oh MH, et al. Remarkable Effect of Gefitinib Retreatment in a Lung Cancer Patient With Lepidic Predominat Adenocarcinoma who had Experienced Favorable Results From Initial Treatment With Gefitinib: A Case Report. J Clin Med Res. 2012; 4: 216-20. [PubMed] [Google Scholar]
  75. Meric JB, Faivre S, Monnerat C, Adi Vago N, Le Chevalier T, Armand JP, et al. [Zd 1839 “Iressa"]. Bull Cancer. 2000; 87: 873-6. [PubMed] [Google Scholar]
  76. Anderson NG, Ahmad T, Chan K, Dobson R, Bundred NJ. ZD1839 (Iressa), a novel epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, potently inhibits the growth of EGFR-positive cancer cell lines with or without erbB2 overexpression. Int J Cancer. 2001; 94: 774-82. [CrossRef] [PubMed] [Google Scholar]
  77. Baselga J, Rischin D, Ranson M, Calvert H, Raymond E, Kieback DG, et al. Phase I safety, pharmacokinetic, and pharma-codynamic trial of ZD1839, a selective oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with five selected solid tumor types. J Clin Oncol. 2002; 20: 4292-302. [CrossRef] [PubMed] [Google Scholar]
  78. Fukuoka M, Yano S, Giaccone G, Tamura T, Nakagawa K, Douillard JY, et al. Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer (The IDEAL 1 Trial) [corrected]. J Clin Oncol. 2003; 21: 2237-46. [CrossRef] [PubMed] [Google Scholar]
  79. Kris MG, Natale RB, Herbst RS, Lynch TJ Jr., Prager D, Belani CP, et al. Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial. JAMA. 2003; 290: 2149-58. [CrossRef] [PubMed] [Google Scholar]
  80. von Minckwitz G, Jonat W, Fasching P, du Bois A, Kleeberg U, Luck HJ, et al. A multicentre phase II study on gefitinib in taxane-and anthracycline-pretreated metastatic breast cancer. Breast Cancer Res Treat. 2005; 89: 165-72. [CrossRef] [PubMed] [Google Scholar]
  81. Schiff BA, McMurphy AB, Jasser SA, Younes MN, Doan D, Yigitbasi OG, et al. Epidermal growth factor receptor (EGFR) is overexpressed in anaplastic thyroid cancer, and the EGFR inhibitor gefitinib inhibits the growth of anaplastic thyroid cancer. Clin Cancer Res. 2004; 10: 8594-602. [CrossRef] [PubMed] [Google Scholar]
  82. Shi L, Tang J, Tong L, Liu Z. Risk of interstitial lung disease with gefitinib and erlotinib in advanced non-small cell lung cancer: a systematic review and meta-analysis of clinical trials. Lung Cancer. 2014; 83: 231-9. [CrossRef] [PubMed] [Google Scholar]
  83. Shi Y, Sun Y, Yu J, Ding C, Wang Z, Wang C, et al. China experts consensus on the diagnosis and treatment of advanced stage primary lung cancer (2016 version). Asia Pac J Clin Oncol. 2017; 13: 87-103. [CrossRef] [PubMed] [Google Scholar]
  84. Han SY, Zhao MB, Zhuang GB, Li PP. Marsdenia tenacissima extract restored gefitinib sensitivity in resistant non-small cell lung cancer cells. Lung Cancer. 2012; 75: 30-7. [CrossRef] [PubMed] [Google Scholar]
  85. Grigoriu B, Berghmans T, Meert AP. Management of EGFR mutated nonsmall cell lung carcinoma patients. Eur Respir J. 2015; 45: 1132-41. [CrossRef] [PubMed] [Google Scholar]
  86. Dhillon S. Gefitinib: a review of its use in adults with advanced non-small cell lung cancer. Target Oncol. 2015; 10: 153-70. [CrossRef] [PubMed] [Google Scholar]
  87. Li F, Zhu T, Cao B, Wang J, Liang L. Apatinib enhances antitu-mour activity of EGFR-TKIs in non-small cell lung cancer with EGFR-TKI resistance. Eur J Cancer. 2017; 84: 184-92. [CrossRef] [PubMed] [Google Scholar]
  88. Abbruzzese JL, Grunewald R, Weeks EA, Gravel D, Adams T, Nowak B, et al. A phase I clinical, plasma, and cellular pharmacology study of gemcitabine. J Clin Oncol. 1991; 9: 491-8. [CrossRef] [PubMed] [Google Scholar]
  89. Csoka K, Liliemark J, Larsson R, Nygren P. Evaluation of the cytotoxic activity of gemcitabine in primary cultures of tumor cells from patients with hematologic or solid tumors. Semin Oncol. 1995; 22: 47-53. [Google Scholar]
  90. Pollera CF, Ceribelli A, Crecco M, Oliva C, Calabresi F. Prolonged infusion gemcitabine: a clinical phase I study at low-(300 mg/m2) and high-dose (875 mg/m2) levels. Invest New Drugs. 1997; 15: 115-21. [CrossRef] [PubMed] [Google Scholar]
  91. Siegel R, DeSantis C, Virgo K, Stein K, Mariotto A, Smith T, et al. Cancer treatment and survivorship statistics, 2012. CA Cancer J Clin. 2012; 62: 220-41. [CrossRef] [PubMed] [Google Scholar]
  92. Vincent A, Herman J, Schulick R, Hruban RH, Goggins M. Pancreatic cancer. Lancet. 2011; 378: 607-20. [CrossRef] [PubMed] [Google Scholar]
  93. Paez D, Labonte MJ, Lenz HJ. Pancreatic cancer: medical management (novel chemotherapeutics). Gastroenterol Clin North Am. 2012; 41: 189-209. [CrossRef] [PubMed] [Google Scholar]
  94. Heinemann V. Gemcitabine in the treatment of advanced pancreatic cancer: a comparative analysis of randomized trials. Semin Oncol. 2002; 29: 9-16. [CrossRef] [EDP Sciences] [PubMed] [Google Scholar]
  95. Erten C, Demir L, Somali I, Alacacioglu A, Kucukzeybek Y, Akyol M, et al. Cisplatin plus gemcitabine for treatment of breast cancer patients with brain metastases; a preferential option for triple negative patients? Asian Pac J Cancer Prev. 2013; 14: 3711-7. [CrossRef] [PubMed] [Google Scholar]
  96. Franchina T, Adamo B, Ricciardi GR, Caristi N, Agostino RM, Proto C, et al. Activity of pegylated liposomal doxorubicin in combination with gemcitabine in triple negative breast cancer with skin involvement: two case reports. Cancer Biol Ther. 2012; 13: 472-6. [CrossRef] [PubMed] [Google Scholar]
  97. Kim M, Chin YW, Lee EJ. alpha, gamma-Mangostins Induces Autophagy and Shows Synergistic Effectwith Gemcitabine in Pancreatic Cancer Cell Lines. Biomol Ther. (Seoul) 2017. [PubMed] [Google Scholar]
  98. Herrmann R, Bodoky G, Ruhstaller T, Glimelius B, Bajetta E, Schuller J, et al. Gemcitabine plus capecitabine compared with gemcitabine alone in advanced pancreatic cancer: a randomized, multicenter, phase III trial of the Swiss Group for Clinical Cancer Research and the Central European Cooperative Oncology Group. J Clin Oncol. 2007; 25: 2212-7. [CrossRef] [PubMed] [Google Scholar]
  99. Heinemann V, Quietzsch D, Gieseler F, Gonnermann M, Schonekas H, Rost A, et al. Randomized phase III trial of gemcit-abine plus cisplatin compared with gemcitabine alone in advanced pancreatic cancer. J Clin Oncol. 2006; 24: 3946-52. [CrossRef] [PubMed] [Google Scholar]
  100. Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007; 25: 1960-6. [CrossRef] [PubMed] [Google Scholar]
  101. Wang Y, Schmid-Bindert G, Zhou C. Erlotinib in the treatment of advanced non-small cell lung cancer: an update for clinicians. Ther Adv Med Oncol. 2012; 4: 19-29. [CrossRef] [PubMed] [Google Scholar]
  102. Abera MB, Kazanietz MG. Protein kinase Calpha mediates erlo-tinib resistance in lung cancer cells. Mol Pharmacol. 2015; 87: 832-41. [CrossRef] [PubMed] [Google Scholar]
  103. Zhao J, Guerrero A, Kelnar K, Peltier HJ, Bader AG. Synergy between next generation EGFR tyrosine kinase inhibitors and miR-34a in the inhibition of non-small cell lung cancer. Lung Cancer. 2017; 108: 96-102. [CrossRef] [PubMed] [Google Scholar]
  104. Lee CB, Stinchcombe TE, Rosenman JG, Socinski MA. Therapeutic advances in local-regional therapy for stage III non-small-cell lung cancer: evolving role of dose-escalated conformal (3-dimen-sional) radiation therapy. Clin Lung Cancer. 2006; 8: 195-202. [CrossRef] [PubMed] [Google Scholar]
  105. Roswit B, Patno ME, Rapp R, Veinbergs A, Feder B, Stuhlbarg J, et al. The survival of patients with inoperable lung cancer: a large-scale randomized study of radiation therapy versus placebo. Radiology. 1968; 90: 688-97. [CrossRef] [PubMed] [Google Scholar]
  106. Johnson DH, Einhorn LH, Bartolucci A, Birch R, Omura G, Perez CA, et al. Thoracic radiotherapy does not prolong survival in patients with locally advanced, unresectable non-small cell lung cancer. Ann Intern Med. 1990; 113: 33-8. [CrossRef] [PubMed] [Google Scholar]
  107. Dillman RO, Berry C, Ryan KP, Green MR, Seagren SL. Recent outcomes for patients with carcinoma of the lung. Cancer Invest. 1991; 9: 9-17. [CrossRef] [PubMed] [Google Scholar]
  108. Payne DG. Non-small-cell lung cancer: should unresectable stage III patients routinely receive high-dose radiation therapy? J Clin Oncol. 1988; 6: 552-8. [CrossRef] [PubMed] [Google Scholar]
  109. Jung JW, Hwang SY, Hwang JS, Oh ES, Park S, Han IO. Ionising radiation induces changes associated with epithelial-mesenchymal transdifferentiation and increased cell motility of A549 lung epithelial cells. Eur J Cancer. 2007; 43: 1214-24. [CrossRef] [PubMed] [Google Scholar]
  110. Wild-Bode C, Weller M, Rimner A, Dichgans J, Wick W. Sublethal irradiation promotes migration and invasiveness of glioma cells: implications for radiotherapy of human glioblastoma. Cancer Res. 2001; 61: 2744-50. [Google Scholar]
  111. Camphausen K, Moses MA, Beecken WD, Khan MK, Folkman J, O'Reilly MS. Radiation therapy to a primary tumor accelerates metastatic growth in mice. Cancer Res. 2001; 61: 2207-11. [Google Scholar]
  112. Giaccone G. Clinical impact of novel treatment strategies. Onco-gene. 2002; 21: 6970-81. [CrossRef] [Google Scholar]
  113. Marino P, Preatoni A, Cantoni A. Randomized trials of radiotherapy alone versus combined chemotherapy and radiotherapy in stages IIIa and IIIb nonsmall cell lung cancer. A meta-analysis. Cancer. 1995; 76: 593-601. [Google Scholar]
  114. Sause WT, Scott C, Taylor S, Johnson D, Livingston R, Komaki R, et al. Radiation Therapy Oncology Group (RT0G) 88-08 and Eastern Cooperative Oncology Group (EC0G) 4588: preliminary results of a phase III trial in regionally advanced, unresectable non-small-cell lung cancer. J Natl Cancer Inst. 1995; 87: 198-205. [CrossRef] [PubMed] [Google Scholar]
  115. Zhang T, Cui GB, Zhang J, Zhang F, Zhou YA, Jiang T, et al. Inhibition of PI3 kinases enhances the sensitivity of non-small cell lung cancer cells to ionizing radiation. Oncol Rep. 2010; 24: 1683-9. [PubMed] [Google Scholar]
  116. Park SY, Kim YM, Pyo H. Gefitinib radiosensitizes non-small cell lung cancer cells through inhibition of ataxia telangiectasia mutated. Mol Cancer. 2010; 9: 222. [CrossRef] [PubMed] [Google Scholar]
  117. Hsiao WL, Liu L. The role of traditional Chinese herbal medicines in cancer therapy--from TCM theory to mechanistic insights. Plan-ta Med. 2010; 76: 1118-31. [CrossRef] [Google Scholar]
  118. Harvey AL, Cree IA. High-throughput screening of natural products for cancer therapy. Planta Med. 2010; 76: 1080-6. [CrossRef] [PubMed] [Google Scholar]
  119. Aravindaram K, Yang NS. Anti-inflammatory plant natural products for cancer therapy. Planta Med. 2010; 76: 1103-17. [CrossRef] [PubMed] [Google Scholar]
  120. Meijer L, Borgne A, Mulner O, Chong JP, Blow JJ, Inagaki N, et al. Biochemical and cellular effects of roscovitine, a potent and selective inhibitor of the cyclin-dependent kinases cdc2, cdk2 and cdk5. Eur J Biochem. 1997; 243: 527-36. [CrossRef] [PubMed] [Google Scholar]
  121. Tirado OM, Mateo-Lozano S, Notario V. Roscovitine is an effective inducer of apoptosis of Ewing’s sarcoma family tumor cells in vitro and in vivo. Cancer Res. 2005; 65: 9320-7. [CrossRef] [Google Scholar]
  122. Mohapatra S, Chu B, Zhao X, Pledger WJ. Accumulation of p53 and reductions in XIAP abundance promote the apoptosis of prostate cancer cells. Cancer Res. 2005; 65: 7717-23. [CrossRef] [Google Scholar]
  123. Lacrima K, Valentini A, Lambertini C, Taborelli M, Rinaldi A, Zucca E, et al. In vitro activity of cyclin-dependent kinase inhibitor CYC202 (Seliciclib, R-roscovitine) in mantle cell lymphomas. Ann Oncol. 2005; 16: 1169-76. [CrossRef] [PubMed] [Google Scholar]
  124. Zhang F, Zhang T, Gu ZP, Zhou YA, Han Y, Li XF, et al. Enhancement of radiosensitivity by roscovitine pretreatment in human non-small cell lung cancer A549 cells. J Radiat Res. (Tokyo) 2008; 49: 541-8. [CrossRef] [Google Scholar]
  125. Zhang F, Zhang T, Jiang T, Zhang R, Teng ZH, Li C, et al. Wort-mannin potentiates roscovitine-induced growth inhibition in human solid tumor cells by repressing PI3K/Akt pathway. Cancer Lett. 2009; 286: 232-9. [CrossRef] [Google Scholar]
  126. Park SE, Yoo HS, Jin CY, Hong SH, Lee YW, Kim BW, et al. Induction of apoptosis and inhibition of telomerase activity in human lung carcinoma cells by the water extract of Cordyceps militaris. Food Chem Toxicol. 2009; 47: 1667-75. [CrossRef] [PubMed] [Google Scholar]
  127. McCubrey JA, Lertpiriyapong K, Steelman LS, Abrams SL, Yang LV, Murata RM, et al. Effects of resveratrol, curcumin, ber-berine and other nutraceuticals on aging, cancer development, cancer stem cells and microRNAs. Aging (Albany NY) 2017; 9: 1477-536. [Google Scholar]
  128. Aggarwal BB, Bhardwaj A, Aggarwal RS, Seeram NP, Shishodia S, Takada Y. Role of resveratrol in prevention and therapy of cancer: preclinical and clinical studies. Anticancer Res. 2004; 24: 2783-840. [PubMed] [Google Scholar]
  129. Soleas GJ, Diamandis EP, Goldberg DM. Resveratrol: a molecule whose time has come? And gone? Clin Biochem. 1997; 30: 91-113. [CrossRef] [PubMed] [Google Scholar]
  130. Smoliga JM, Baur JA, Hausenblas HA. Resveratrol and health--a comprehensive review of human clinical trials. Mol Nutr Food Res. 2011; 55: 1129-41. [CrossRef] [PubMed] [Google Scholar]
  131. Athar M, Back JH, Tang X, Kim KH, Kopelovich L, Bickers DR, et al. Resveratrol: a review of preclinical studies for human cancer prevention. Toxicol Appl Pharmacol. 2007; 224: 274-83. [CrossRef] [PubMed] [Google Scholar]
  132. Stef G, Csiszar A, Lerea K, Ungvari Z, Veress G. Resveratrol inhibits aggregation of platelets from high-risk cardiac patients with aspirin resistance. J Cardiovasc Pharmacol. 2006; 48: 1-5. [CrossRef] [EDP Sciences] [PubMed] [Google Scholar]
  133. Bhat KPL, Kosmeder JW, 2nd, Pezzuto JM. Biological effects of resveratrol. Antioxid Redox Signal. 2001; 3: 1041-64. [CrossRef] [PubMed] [Google Scholar]
  134. Whyte L, Huang YY, Torres K, Mehta RG. Molecular mechanisms of resveratrol action in lung cancer cells using dual protein and microarray analyses. Cancer Res. 2007; 67: 12007-17. [CrossRef] [Google Scholar]
  135. Kim YA, Lee WH, Choi TH, Rhee SH, Park KY, Choi YH. Involvement of p21WAF1/CIp1, pRB, Bax and NF-kappaB in induction of growth arrest and apoptosis by resveratrol in human lung carcinoma A549 cells. Int J Oncol. 2003; 23: 1143-9. [PubMed] [Google Scholar]
  136. Patel KR, Brown VA, Jones DJ, Britton RG, Hemingway D, Miller AS, et al. Clinical pharmacology of resveratrol and its metabolites in colorectal cancer patients. Cancer Res. 2010; 70: 7392-9. [CrossRef] [Google Scholar]
  137. Zhu J, Song X, Lin HP, Young DC, Yan S, Marquez VE, et al. Using cyclooxygenase-2 inhibitors as molecular platforms to develop a new class of apoptosis-inducing agents. J Natl Cancer Inst. 2002; 94: 1745-57. [CrossRef] [PubMed] [Google Scholar]
  138. Zhu J, Huang JW, Tseng PH, Yang YT, Fowble J, Shiau CW, et al. From the cyclooxygenase-2 inhibitor celecoxib to a novel class of 3-phosphoinositide-dependent protein kinase-1 inhibitors. Cancer Res. 2004; 64: 4309-18. [CrossRef] [Google Scholar]
  139. Kucab JE, Lee C, Chen CS, Zhu J, Gilks CB, Cheang M, et al. Celecoxib analogues disrupt Akt signaling, which is commonly activated in primary breast tumours. Breast Cancer Res. 2005; 7:R796-807. [CrossRef] [PubMed] [Google Scholar]
  140. Tong Z, Wu X, Chen CS, Kehrer JP. Cytotoxicity of a non-cy-clooxygenase-2 inhibitory derivative of celecoxib in non-small-cell lung cancer A549 cells. Lung Cancer. 2006; 52: 117-24. [CrossRef] [PubMed] [Google Scholar]
  141. Tan YH, Lee KH, Lin T, Sun YC, Hsieh-Li HM, Juan HF, et al. Cytotoxicity and proteomics analyses of OSU03013 in lung cancer. Clin Cancer Res. 2008; 14: 1823-30. [CrossRef] [PubMed] [Google Scholar]
  142. Lu J, Papp LV, Fang J, Rodriguez-Nieto S, Zhivotovsky B, Holmgren A. Inhibition of Mammalian thioredoxin reductase by some flavonoids: implications for myricetin and quercetin antican-cer activity. Cancer Res. 2006; 66: 4410-8. [CrossRef] [Google Scholar]
  143. Zhang Q, Zhao XH, Wang ZJ. Flavones and flavonols exert cy-totoxic effects on a human oesophageal adenocarcinoma cell line (OE33) by causing G2/M arrest and inducing apoptosis. Food Chem Toxicol. 2008; 46: 2042-53. [CrossRef] [PubMed] [Google Scholar]
  144. Nadova S, Miadokova E, Cipak L. Flavonoids potentiate the efficacy of cytarabine through modulation of drug-induced apoptosis. Neoplasma. 2007; 54: 202-6. [PubMed] [Google Scholar]
  145. Wang ZH, Kang KA, Zhang R, Piao MJ, Jo SH, Kim JS, et al. Myricetin suppresses oxidative stress-induced cell damage via both direct and indirect antioxidant action. Environ Toxicol Phar. 2010; 29: 12-18. [CrossRef] [Google Scholar]
  146. Shvarev IF, Tsetlin AL. [Anti-blastic properties of berberine and its derivatives]. Farmakol Toksikol 1972; 35: 73-5. [PubMed] [Google Scholar]
  147. Ikram M.A. review on the chemical and pharmacological aspects of genus Berberis. Planta Med. 1975; 28: 353-8. [CrossRef] [PubMed] [Google Scholar]
  148. Creasey WA. Biochemical effects of berberine. Biochem Pharmacol. 1979; 28: 1081-4. [CrossRef] [PubMed] [Google Scholar]
  149. Ivanovska N, Philipov S. Study on the anti-inflammatory action of Berberis vulgaris root extract, alkaloid fractions and pure alkaloids. Int J Immunopharmacol. 1996; 18: 553-61. [CrossRef] [PubMed] [Google Scholar]
  150. Peng PL, Hsieh YS, Wang CJ, Hsu JL, Chou FP. Inhibitory effect of berberine on the invasion of human lung cancer cells via decreased productions of urokinase-plasminogen activator and matrix metalloproteinase-2. Toxicol Appl Pharmacol. 2006; 214: 8-15. [CrossRef] [PubMed] [Google Scholar]
  151. Jin P, Zhang C, Li N. Berberine exhibits antitumor effects in human ovarian cancer cells. Anticancer Agents Med Chem. 2015; 15: 511-6. [CrossRef] [Google Scholar]
  152. Wang K, Zhang C, Bao J, Jia X, Liang Y, Wang X, et al. Synergistic chemopreventive effects of curcumin and berberine on human breast cancer cells through induction of apoptosis and autophagic cell death. Sci Rep. 2016; 6: 26064. [CrossRef] [PubMed] [Google Scholar]
  153. Lee TH, Lee CK, Tsou WL, Liu SY, Kuo MT, Wen WC. A new cytotoxic agent from solid-state fermented mycelium of Antrodia camphorata. Planta Med. 2007; 73: 1412-5. [CrossRef] [PubMed] [Google Scholar]
  154. Kumar VB, Yuan TC, Liou JW, Yang CJ, Sung PJ, Weng CF. An-troquinonol inhibits NSCLC proliferation by altering PI3K/mT0R proteins and miRNA expression profiles. Mutat Res. 2011; 707: 42-52. [CrossRef] [PubMed] [Google Scholar]
  155. Chiang PC, Lin SC, Pan SL, Kuo CH, Tsai IL, Kuo MT, et al. Antroquinonol displays anticancer potential against human hepato-cellular carcinoma cells: a crucial role of AMPK and mT0R pathways. Biochem Pharmacol 2010; 79: 162-71. [CrossRef] [PubMed] [Google Scholar]
  156. Yu CC, Chiang PC, Lu PH, Kuo MT, Wen WC, Chen P, et al. Antroquinonol, a natural ubiquinone derivative, induces a cross talk between apoptosis, autophagy and senescence in human pancreatic carcinoma cells. J Nutr Biochem. 2012; 23: 900-7. [CrossRef] [PubMed] [Google Scholar]
  157. Lin HC, Lin MH, Liao JH, Wu TH, Lee TH, Mi FL, et al. Antroquinonol, a Ubiquinone Derivative from the Mushroom Antrodia camphorata, Inhibits Colon Cancer Stem Cell-like Properties: Insights into the Molecular Mechanism and Inhibitory Targets. J Agric Food Chem. 2017; 65: 51-59. [CrossRef] [PubMed] [Google Scholar]

All Tables

Table 1

- Current regimen of treatment for lung cancer.

All Figures

thumbnail Fig. 1

Chemical structures of anti-tumour agents with clinical applications.

In the text

Current usage metrics show cumulative count of Article Views (full-text article views including HTML views, PDF and ePub downloads, according to the available data) and Abstracts Views on Vision4Press platform.

Data correspond to usage on the plateform after 2015. The current usage metrics is available 48-96 hours after online publication and is updated daily on week days.

Initial download of the metrics may take a while.