Current Cancer Drug Targets - Volume 17, Issue 8, 2017

Background: Interleukin 12 (IL-12) is a pleiotropic cytokine that plays an essential role in Th1-type immune response against cancer, a condition where cells in a particular part of the body grow and reproduce uncontrollably. Methods: In this review, we describe the structural features of IL-12 family and their roles involved in cancer. Results: IL-12 has been demonstrated to regulate both innate (natural killer cells) and adaptive (cytotoxic T lymphocytes) immunities in cancer therapy. This cytokine has been proposed as a potential new agent to be developed in cancer immunotherapy studies due to its impressive antitumor effects in many animal models. In addition, the antitumor activity of IL-12 can be efficiently induced by itself as well as significantly improved by its combination with various treatment modalities including antibodies, antiangiogenic agents, radiotherapy, adoptive therapy, and anti-tumor vaccines. Conclusion: IL-12 has potential roles in anticancer therapy. The advantages of using immunotherapeutic approaches in clinical trials have been reported recently. However, the mechanisms to underlay the immunoregulation and antitumor activities of IL-12 itself, as well as its combination, remain under investigation.

Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide and its incidence is steadily rising. Currently, sorafenib remains the only approved standard treatment for patients with advanced HCC, as it has proven to increase survival in these patients. However, clinical and preclinical observations indicate that sorafenib treatment may have limited efficacy due to tumor progression from the rapid development of acquired resistance. Elucidation of the underlying mechanisms of evasive resistance to sorafenib is a major challenge in HCC research. In recent years, the role of epithelial-to-mesenchymal transition (EMT) in the advancement of HCC and development of drug resistance has gained increasing attention. EMT is a developmental multistep molecular and cellular reprogramming process that is hijacked by cancer cells to enable aggressiveness. In this review, we provide an overview of the currently available preclinical studies on the EMT mechanisms underlying resistance to sorafenib treatment. Recent studies report enrichment of cancer stem cells (CSCs) after sorafenib treatment. Interestingly, EMT process has been implicated in the generation of CSCs associated with therapy resistance. We discuss how combination of sorafenib with EMT inhibitors could enhance the clinical response to sorafenib, resulting in longer duration of responses, than observed with sorafenib monotherapy. In particular, we discuss how these new insights may facilitate rational development of combination therapies in the future to impact survival of patients with advanced HCC.

Background: Mutations in proto-oncogenes and tumor suppressor genes make cancer cells proliferate indefinitely. As they possess almost all mechanisms for cell proliferation and survival like healthy cells, it is difficult to specifically target cancer cells in the body. Current treatments in most of the cases are harmful to healthy cells as well. Thus, it would be of great prudence to target specific characters of cancer cells. Since cancer cells avidly use glucose and glutamine to survive and proliferate by upregulating the relevant enzymes and their specific isoforms having important regulatory roles, it has been of great interest recently to target the energy-related metabolic pathways as part of the therapeutic interventions. Objective: This paper summarizes the isozymes overexpressed in breast cancer, their roles of energy metabolism and cross-talks with other important signaling pathways in regulating proliferation, invasion and metastasis in breast cancer. Method: Information has been collected from recently published literature available on Google Scholar and PubMed. Where available, in vivo results were given more importance over in vitro works. Result: Like many other cancers, breast cancer shows increased dependence on glycolysis rather than mitochondrial respiration, the main energy source in healthy cells. Cancer cells alter the cellular energy system in a way that helps minimize level of reactive oxygen species and simultaneously produce enough macromolecules- proteins, lipids and nucleotides for cellular proliferation. The altered system enables the cells to grow, proliferate, metastasize and to develop drug resistance. Certain isozymes of metabolic enzymes are overexpressed in breast cancer and the degree of expression of these enzymes vary among subtypes. Conclusion: A clear understanding of the variations of energy metabolism in different molecular subtypes of breast cancer would help in treating each type with a very customized, safer and efficient treatment regimen. Anti-cancer drugs or RNAi or combination of both targeting cancer cell specific isozymes of metabolic enzymes mentioned in this article could offer a great treatment modality for breast cancer.

Background: Natural products showed anticancer activity and often induce apoptosis or autophagy in cancer cells through the PI3K/Akt/mTOR signaling pathways. The potential of natural products as PI3Ks inhibitors has been reported, which suggest PI3Ks a promising anticancer target. Phosphoinositide 3-kinase is a family of related intracellular signal transducer enzymes or lipid kinases that regulate different cellular processes involved in cancer. Objective: To identify the molecular reason behind the similar target based activity of selected shikimate pathway metabolites on PI3Kγ, a detail structure-activity relationship study was performed. Method: In the studied work, anticancer potential of plant molecules gallic acid and serpentine was evaluated against PI3Kγ isoform and compared with wortmannin, a steroid metabolite of the fungi and a non-specific covalent known inhibitor of PI3Ks by using in-silico QSAR, docking, ADMET, chemical isolation from plant, NMR and in-vitro activity. Results: A predictive QSAR model was developed by applying multiple linear regression which revealed identification of key structural properties regulating the inhibitory activity of serpentine and gallic acid on PI3Kγ. The model exhibited acceptable statistical parameters such as r2 0.76, r2CV 0.72, and q2 0.55. Structural elucidation was done through NMR studies. Predicted activities were further evaluated through in-vitro testing of gallic acid and serpentine targeting PI3Kγ. Conclusion: The identified chemical features modulating the activity were amide, amine, and secondary amine groups counts, highest occupied molecule orbital (HOMO) energy and valence connectivity index (order 2). In-silico ADME and toxicity risk assessment was done for pharmacokinetic and bioavailability compliance evaluation.

Background: Commonly used methods for analyzing interactivity between drugs (e.g. synergy, antagonism) such as isobologram, combination index, and curve shift are based on the Loewe Additivity principle of dose equivalence and the inherent assumption of similar concentration- effect (C-E) including parallel curves and equal maximum effects (Emax), and therefore are not suitable for drugs with dissimilar C-E. This study describes a new method that is without this limitation and has the additional advantage of enabling statistical analysis. Methods and Results: The method comprises two steps. First, based on the dose equivalence principle, the experimentally obtained C-E of one drug was used to calculate the equally effective C-E of the other drug at no interactivity; the resulting two zero-interactivity C-E formed the upper and lower boundaries of Additivity Envelope. Next, 95% confidence intervals calculated from experimental data were added to Additivity Envelope to obtain Uncertainty Envelope (UE). Experimentally observed effects of drug combinations (C-Ecomb,observed) located within UE indicate additivity whereas C-Ecomb,observed located above or below UE indicate statistically significant (p<0.05) synergy or antagonism, respectively. Additional in silico studies demonstrated the shape and size of Additivity Envelope, which determines the ability to detect drug interactivity, depended on the Drug A-to-B concentration ratios and the ratios of their C-E curve shape parameter. Analyses of experimental results of combinations of drugs with nonparallel C-E and/or unequal Emax indicated UE as more versatile and provided more information, compared to earlier methods. Conclusion: UE is a broadly applicable method for analysis, including statistical significance assessment, of drug interactivity.

Background: Breast cancer is the most diagnosed and the major cause of cancer death in women worldwide. Metastasis is the main cause of these deaths. The metastatic cascade involves multiple steps and it has been described that adrenergic receptors can modulate this process at multiple levels. However, β -adrenergic action in breast cancer is controversial. We have previously shown that β-adrenergic agonists inhibit cell proliferation and tumor growth of numerous breast cancer models. Objective: The purpose of the present investigation was to evaluate adrenergic effect in parameters related to tumor progression (migration, invasion and metastases) in two human breast cancer cell lines. Methods: Migration was assessed in IBH-6 and MDA-MB-231 cells by time-lapse videomicroscopy and modified Boyden chambers. Invasion was evaluated by Transwells coated with Matrigel and expression of pro-metastatic genes was determined by RT-qPCR. Experimental metastases studies were performed by injection of the cells in the tail vein of NSG immuno-deficient mice. Results: In both cell lines, salbutamol (β2-agonist) and propranolol (β-blocker) significantly diminished cell migration while epinephrine exerted opposite effects. Moreover, salbutamol inhibited invasion of both breast cancer cell lines and enhanced adhesion to extracellular matrix. Salbutamol treatment was also able to decrease the expression of pro-metastatic genes in MDA-MB-231 cells. Finally, this compound decreased the number and size of MDA-MB-231 lung experimental metastases in NSG immuno- deficient mice. No effect on the establishment of IBH-6 metastases was observed. Conclusion: Our results suggest that salbutamol could be an effective adjuvant drug for the treatment of metastatic breast cancer.