Current Cancer Drug Targets - Volume 17, Issue 4, 2017

Background: Silencing of two or more complementary signaling pathways can lead to cell death, while loss of any single genetic function does not show a severe phnotype, this kind of inter action is coined as “synthetic lethality”. Nowadays, synthetic lethality has become a widely used anti-cancer strategy. Method: We reviewed the synthetic lethal interactions exploited in anticancer therapies before 2016. Conclusion: Synthetic lethality is a well proved anticancer strategy and more synthetic lethal interactions is being translated into clinical cancer therapies.

Introduction: Antineoplastic agents affect the cardiovascular system, and the incidence of cardiotoxicity is continuously growing in patients with hematologic malignancies and treated with antineoplastic therapy. Methods: In this mini-review, we analyzed existing literature which evaluates the likelihood of cardiotoxicity related to the main agents employed in the treatment of hematologic malignancies. Results: There is a significant need to optimize the early identification of patients who are at risk of cardiotoxicity. The conventional echocardiographic measurements used to detect cardiac alterations, such as LVEF, fractional shortening, diameters and volumes, allow only a late diagnosis of cardiac dysfunction, which might be already irreversible. The early identification of patients at risk for rapid progression towards irreversible cardiac failure has a primary purpose, the opportunity for them to benefit from early preventive and therapeutic measures. A useful imaging technique that points in this direction detecting subclinical LVD may be the speckle tracking echocardiography, that has demonstrated a previous detection of myocardial contractile dysfunction compared to the traditional left ventricular ejection fraction. In this view, the discovery of new biomarkers to identify patients at a high risk for the development of these complications is another priority. Conclusion: Cardiotoxicity induced by anticancer drugs is always the outcome of several concurrent factors. It is plausible that an asymptomatic dysfunction precedes clinical events. During this asymptomatic phase, an early treatment prepares the patient for cardiovascular “safety” conditions; on the other hand, a late or missing treatment paves the ground for the development of future cardiac events.

Background: It is widely accepted that chronic inflammation critically contributes to cancer. Immune tolerance in cancer mediates tumor escape from the immune system. The mechanisms of relations between inflammation and immune tolerance are still not fully elucidated. Objective: The main mechanisms that link inflammation and tolerance are considered. Drug targets that are in use to interfere with inflammation in cancer are discussed. Conclusion: Inflammation mediates tumor-induced tolerance. The induction and the maintenance of the chronic inflammatory response is a universal mechanism of immune tolerance.

In the recent years, significant development of molecular genetics has contributed to the better understanding of leukemogenesis and classification of the different leukemia subtypes. Patients diagnosed with acute leukemia usually undergo chemotherapy, which involves the induction of remission, consolidation of remission and maintenance therapy. Patients are still vulnerable to relapse due to differences in the sensitivity of leukemia cells to the chemotherapeutic agent, because of the active drugs removal from the cells, improving the repair of DNA damage or abnormalities in the apoptotic pathway. Cell adhesion and miRNA expression level also affect the drug resistance. New candidate genes and genes correlated with the disease have been sought to increase the survival of patients with leukemia. Candidate gene is usuallysion product regulates disease progression. There are classic and digital methods of finding cand a loci located in a certain chromosomal region suspected of involvement to the disease course or its expresidate genes. These techniques are inexpensive, quick and easy to carry out. Unfortunately, due to insufficient knowledge of the disease etiology and low accuracy, researchers cannot detect all genes, involved in leukemogenesis and cell resistance. Currently, scientists have many tools used for selecting genes, such as expression microarrays, comparative genomic hybridization and next generation sequencing. Among the validation techniques for candidate genes, the mostly used ones are fluorescent in situ hybridization and real-time PCR. In our review we present 18 candidate genes of resistance to therapy in childhood leukemia.

Background: Breast cancer is the most frequently diagnosed life-threatening malignancy among women, across the globe. HER2 positive is a distinct breast cancer subtype, on account of its unique biology and physiological behavior. Results: Amplification of HER2 oncogene/polysomy 17 leads to HER2 overexpression that is a significant causal implication in HER2 positive breast cancer. HER2 gene variants, as well as other genes/gene variants, are involved in its overexpression, disease prognosis and in predicting the susceptibility towards HER2 positive breast cancer. Trastuzumab (Herceptin) is the most commonly used therapy for treating patients with HER2 positive status. Genomic alterations are incriminated in the development of trastuzumab-resistance, which influences the response towards trastuzumab-therapy. Conclusion: In the current review article, we have summarized the genomic alterations that are responsible for overexpression of HER2 and therefore, increased risk of breast cancer. In addition, the gene variants affecting response towards trastuzumab-therapy have also been discussed.

Background: A number of chemically diverse substances bind to the tubulin and inhibit cell proliferation by disrupting microtubule dynamics. There are four binding sites for the ligands binding to the tubulin; taxane/epothilone and laulimalide/peloruside binding ligands stabilize microtubule while vinca and colchicine binding site agents promote microtubule depolymerization. Most of the tubulin binding ligands disturb the tubulin-microtubule dynamic equilibrium but these may exhibit anticancer activities through different mechanisms. Taxanes and epothilones are widely used cytotoxic agents and are found effective against different types of human malignancies. However, taxanes are susceptible to pgp mediated multi-drug resistance, dose limiting hematopoietic toxicity and cumulative neurotoxicity. Vinca alkaloids are already in clinical practice, but ligands binding to the colchicine site are still in the different stages of clinical trials. Objective: In the current review article, plausible mechanistic details about the interactions of ligands at the binding pocket and subsequent changes in the tubulin structure are described. The review article also illustrated different formulations of the tubulin binding agents in combination with other chemotherapeutic agents and their therapeutic potential against various human malignancies. Conclusion: Tubulin targeting agents emerged as one of the most successful anticancer drugs and a number of structurally different chemical compounds are in advance stages of clinical development.

Background: EGFR tyrosine kinase inhibitors (TKIs) are widely used for advanced nonsmall cell lung cancer (NSCLC) patients with a sensitizing EGFR mutation and provide a promising treatment strategy. However, acquired resistance to EGFR-TKIs restricts their application. The mechanisms underlying acquired resistance to TKIs have been explored and Phosphoinositide 3-kinase (PI3K)/Akt/mTOR pathway plays a very important role in NSCLC development as well as EGFR-TKI resistance. Polyphyllin II(PP II) is the main steroidal saponin constituent which derives from the root of Paris polychylia. Objective: We examined the sensitizing effect of PP II to gefitinib on proliferation, apoptosis, PI3K/Akt/mTOR signaling pathway and tumor growth on gefitinib-resistant NSCLC in vitro and in vivo. Methods: Gefitinib-resistant PC-9/ZD cells and gefitinib-sensitive PC-9 cells were used. In the absence of PI3K siRNA, MTT assay, Annexin V/PI analyses, Western blot, and Immunohistochemistry analysis by TUNEL assays for xenograft model were carried out. Results: PP II promoted the anti-proliferative effects of gefitinib and gefitinib-induced apoptosis via activation of caspases and cleavage of PARP. PP II elevated sensitization of gefitinib through targeting the PI3K/Akt/mTOR. PP II with gefitinib treatment was more effective in inhibiting tumor growth and PI3K inactivation on gefitinib-resistant xenograft. Conclusion: The results indicated that PP II elevated sensitization of drug-resistant PC-9/ZD cells to gefitinib through the inhibition of PI3K/Akt/mTOR signaling pathway. It provides a potential new strategy to overcome gefitinib resistance for EGFR-TKI resistant NSCLC.

Background: Aurora A kinase represent a feasible target in cancer therapy. Objective: To evaluate the proteomic response of human liver carcinoma cells to alisertib (ALS) and identify the molecular targets of ALS, we examined the effects of ALS on the proliferation, cell cycle, autophagy, apoptosis, and chemosensitivity in HepG2 cells. Method: The stable-isotope labeling by amino acids in cell culture (SILAC) based quantitative proteomic study was performed to evaluate the proteomic response to ALS. Cell cycle distribution and apoptosis were assessed using flow cytometry and autophagy was determined using flow cytometry and confocal microscopy. Results: Our SILAC proteomic study showed that ALS regulated the expression of 914 proteins, with 407 molecules being up-regulated and 507 molecules being down-regulated in HepG2 cells. Ingenuity pathway analysis (IPA) and KEGG pathway analysis identified 146 and 32 signaling pathways were regulated by ALS, respectively, which were associated with cell survival, programmed cell death, and nutrition-energy metabolism. Subsequently, the verification experiments showed that ALS remarkably arrested HepG2 cells in G2/M phase and led to an accumulation of aneuploidy via regulating the expression of key cell cycle regulators. ALS induced a marked autophagy in a concentration- and time-dependent manner via the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway. Autophagy inhibition promoted the pro-apoptotic effect of ALS, indicating a cyto-protective role of ALS-induced autophagy. ALS increased the chemosensitivity of HepG2 cells to cisplatin and doxorubicin. Conclusion: Taken together, ALS induces autophagy and cell cycle arrest in HepG2 cells via PI3K/Akt/mTOR-mediated pathway. Autophagy inhibition may promote the anticancer effect of ALS and sensitize the chemotherapy in HepG2 cells.