Clinical Cancer Drugs - Volume 7, Issue 1, 2020

More than 90% of new potential therapeutic drugs have failed in clinical trials. In this study, the characteristics of failed new drugs for the treatment of seven types of cancer were first examined, followed by a review of the hazard ratios of survival in typical phase III clinical drug trials of these cancers from the last five years. The data suggested that population sizes in most clinical trials were limited to a certain level of detection. Evidently, each drug has its effect only in certain individuals with defined characteristics, and the success and failure of a new drug depend on these characteristics, such as ethnic group, sex, environmental conditions, pathological features, and genotype. Due to the complexity of the influence of multiple factors and the current limitation in understanding them, a large number of subgroups among patients may not have been recognized. Therefore, any decision only based on a few statistical comparisons, may not always provide correct judgement for a new drug. The drugs that are successful in clinical trials are “winners” regardless of how the differences in genotypes or other characteristics' influence on patients as compared to new drugs and placebos, or new and existing drugs. Drugs that are effective on certain characterizations or a specific group of patients are often categorized as a failure in clinical trials based on the current statistical criteria. Thus, previously failed drugs can be reevaluated and reutilized by analyzing whether these drugs have different effects on various genomic populations, or on patients who may emerge as subgroups based on other variables.

Background: Larynx cancer (LCa) is the most common head and neck cancer and accounts for 1-2.5% of all human cancers worldwide. Metformin, an oral anti-diabetic drug, has been recently shown to have anti-cancer activity in various cancer types, and there are several studies in the literature pointing to its potential to sensitize cancer cells to chemotherapeutic drugs. Objective: This study was aimed at exploring the anti-cancer effects of metformin alone or in combination with 5-fluorouracil (5-FU) on Hep-2 cells. Methods: The effects of metformin and/or 5-FU on the proliferative, clonogenic, and apoptotic potential of Hep-2 cells were evaluated with Cell Viability Detection Kit-8, soft agar assay and Annexin VFITC Apoptosis assay, respectively. Migratory and invasive potential of cells was tested using scratch, transwell migration and Matrigel invasion assays. Gene expression of cells exposed to metformin and/or 5-FU was profiled using RT2 mRNA PCR Array plates. Results: Treatment of Hep-2 cells with metformin inhibited cell proliferation by inducing apoptosis, and suppressed cell migration. Besides, treatment of metformin along with 5-FU improved the antiproliferative and anti-migratory effects of 5-FU. However, unexpectedly, metformin was found to enhance cellular invasion and reverse the inhibitory effect of 5-FU on the invasive potential of Hep-2 cells. Conclusion: Our findings suggest that metformin might be used as an adjuvant agent in the treatment of LCa. However, the potential of metformin to promote the invasion of cancer cells should not be neglected.

Background: Breast Cancer is a recurrent problem across the world. According to a report, breast cancer has the second highest mortality rate in women globally. Despite having an advanced degree of chemotherapy, resistance is developed against the therapies. Studies showed that anthracyclins like doxorubicin used in the treatment of breast cancer are found to develop resistance, which is not easy to identify. Mutations in the tumor suppressor gene P53 are associated with the primary resistance to doxorubicin and thus inducing an early relapse of breast tumors. Resistance against Doxorubicin is not identifiable easily. Development of resistance and metastasis of tumors are the two processes that cannot be separated from each other. It is widely known that endothelium has a major role in controlling metastasis and tumor cell invasion. Endothelial cells express different adhesion molecules during recruitment of leukocytes in localized area, which is called leukocyte extravasation or diapedesis, or leukocyte trans endothelial migration (LEM). LEM (leukocyte trans endothelial migration) plays crucial role in the inflammation of breast cancer tissues. Objective: Predicting the role of deregulation of claudins in leukocyte trans endothelial migration in breast cancer metastasis and resistance. Methods: The breast cancer proteomic metadata was collected and compared among the common candidates. The enrichment analysis of those common candidates was performed using a network analyst. Results: The analysis of breast cancer genes obtained from dbDEPC showed probable involvement of 4 candidate genes belonging to the claudin family. Claudins are responsible for the migration of an increased amount of leukocytes in the breast tumor region, which increases the inflammation and may contribute to worsening the disease progression. Conclusion: We believe these candidates also contribute in the development of resistance to chemotherapy.

Background: Recent human and animal studies have demonstrated the oncostatic properties of N-acetyl-5-methoxytryptamine (melatonin) in different types of cancer. However, in few cancer cell lines including colorectal cancer cell line (HT-29), acute T cell leukemia cell line (JURKAT) and cervical cancer cell line (HeLa), precise oncostatic mechanism induced by melatonin is yet to be described. Objectives: The aim of this study is to investigate the effects of melatonin in HT-29, JURKAT and HeLa cells and to determine the underlying molecular mechanism. Methods: Cell viability was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay while cell cycle, apoptosis and membrane potential were analysed by flow cytometry. Reactive oxygen species (ROS) was detected by 2',7'-dichlorofluorescein diacetate (DCFH-DA) staining. Protein expressions were determined by Western blot. Results: Our results showed that melatonin suppressed cell proliferation, increased the number of sub G1 hypodiploid cells and cell cycle arrest in HT-29, JURKAT and HeLa cells. Besides, melatonin also induced early and late apoptosis, although there were marked variations in responses between different cell lines (sensitivity; HeLa > HT-29 >JURKAT). Apart from that, staining with DCHF-DA demonstrated ROS production that was induced in a dose-dependent manner in HeLa, HT-29 and JURKAT cells. Moreover, the apoptotic process and oncostatic effect of melatonin were seen to be associated with extracellular-signal-regulated kinase (ERK) and stress-activated protein kinase/c-Jun NH (2)-terminal kinase (SAPK-JNK) signalling cascades in HeLa cells. In HT-29 and JURKAT cells, melatonin induced apoptosis via activation of p38 mitogen-activated protein kinases (p38), ERK and SAPK-JNK signalling pathways. In all three cell lines, the apoptotic event was triggered by the mammalian target of rapamycin (mTOR)-mediated activation of the downstream target rapamycininsensitive companion of mTOR (RICTOR) and/or regulatory-associated protein of mTOR (RAPTOR) proteins. Conclusion: Our findings confirm that melatonin induces apoptosis through reactive oxygen speciesmediated dysregulated mitogen-activated protein kinase (MAPK) and mTOR signalling pathways in these cancer cell lines.

Background: Gefitinib was approved by the Food and Drug Administration (FDA) of the United States (US) for the treatment of advanced non-small cell carcinoma harboring sensitizing epidermal growth factor receptor (EGFR) mutations. The use of gastric acid-suppressing medication inhibits gefitinib absorption and reduces its plasma concentration, but retrospective studies on whether there is the corresponding repercussion on progression-free survival (PFS) have yielded variable results, mainly due to heterogeneity in study cohorts and study designs. Objectives: To assess the clinical impact of the use of gastric acid-suppressing medication in patients on first-line gefitinib for NSLC harboring common EGFR mutation. Methods: This is a retrospective cohort study conducted in a single, tertiary referral center in Hong Kong S.A.R., which included 193 Chinese patients with advanced adenocarcinoma of lung harboring common sensitizing EGFR mutations who received gefitinib as the first-line treatment. The progression- free survival (PFS) and overall survival (OS) for patients who took gastric acid-suppressing agents, namely histamine-2 receptor antagonists (H2RA) or proton pump inhibitors (PPI), were compared with those who did not take such medication (control group). Results: Despite the universal practice to separate the medicating time of gastric acid suppressants and EGFR-TKIs by 12 hours, patients who were on gastric acid suppressants had significantly shorter PFS, especially for those on proton pump inhibitor (Median 368 vs. 189 vs. 166 days - For control, H2RA group and PPI group respectively, p-value <0.001). The OS is also significantly shorter for those taking gastric acid suppressants (Median 825 vs. 485 vs. 422 days - For control, H2RA group and PPI group respectively, p-value <0.001). Conclusion: The co-administration of gastric acid suppressants with gefitinib is associated with shorter progression-free survival and overall survival.