Current Cancer Drug Targets - Volume 17, Issue 5, 2017

Background: Cathepsin D (CATD), one of the aspartyl endoproteinase involved in different physiological processes and signaling pathways, is accountable for metabolic breakdown of intracellular proteins, the activation of growth factors, hormones, and precursors of enzyme, the processing of antigens, enzyme inhibitors and activators and the regulation of apoptosis. Implication as a Target: Studies have confirmed the role and significance of CATD in an assortment of pathological conditions like Atherosclerosis, Ainactive proCATD, it undergoes diverse cleavages to attain a desired conformation in an alzheimer, Cancer, Cardiovascular, Huntington and Parkinson diseases. Amalgamated and veiled as cidic milieu to act as a functionally active protein. In search of new candidate target (s) for cancer, CATD has attracted a wide group of investigators across the globe and is being recognized as a well-defined marker in cancer especially for breast and hormone-dependent cancer. Methods: In this review, PubMed, Sci-finder and other search engines were used to gather information on Cathepsin D. The necessary and relevant information was thoroughly studied to make the article appropriate to highlight all the aspects related to Cathepsin D and its role in cancer. Findings & Conclusion: The present review illustrates structural, functional and regulatory aspects of CATD in cancer, its significant role in angiogenesis, metastasis, invasion, apoptosis, cell proliferation, and therapeutic potential besides the benefits of targeting CATD by the natural products in cancer chemoprevention.

Background: CD20 is a surface antigen, which is expressed at certain stages of B-cell differentiation. Targeting the CD20-positive B-cells with therapeutic monoclonal antibodies (MAbs) has been an effectual strategy in the treatment of hematologic malignancies such as non-Hodgkin’s lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Initial success with Rituximab (RTX) has encouraged the creation and development of more effective CD20 based therapeutics. However, treatment with conventional MAbs has not been adequate to overcome the problems such as refractory/ relapsed disease. In this regard, new generations of MAbs with enhanced affinity or improved anti-tumor properties have been developed. Objective: CD20 directed therapeutics have heterogeneous features and mechanisms of action. Hence, having sufficient knowledge on the immunological and molecular aspects of CD20 based cancer therapy is necessary for predicting the clinical outcomes and taking the necessary measures. Method: An extensive search was performed in PubMed and similar databases for peer-reviewed articles concerning the biology, function and characteristics of CD20 molecule as well as the mechanisms of action and evolutionary process of CD20 targeting agents. Results: This review provides information about the current situation of CD20 targeting immunotherapeutics including MAbs, bispecific antibodies (which exert multiple functions or involve Tcells in tumor elimination) and CAR T-cells (engineered T-cells armed with chimeric antigen receptors). Moreover, limitations, challenges and available solutions regarding the application of CD20 targeting treatments are addressed. Conclusion: Utilization of CD20-targeted therapeutics, due to their diverse properties, requires special considerations.

Background: Due to their excellent biocompatibility and biodegradability, poly-epsiloncaprolactone and its derivative copolymers have been extensively studied as drug carriers in pharmaceutical and medical fields, especially for controlled release of anti-tumor drugs. Poly-epsiloncaprolactone based drug delivery systems lead to major advantages including uniform drug distribution, long term of degradation and drug release process, non-toxic in nature and cyto-compatible with body tissues. Approved by US Food and Drug Administration, poly-epsilon-caprolactone provides a promising platform for design and fabrication of anti-tumor drug delivery systems with controllable drug release behaviors. Methods: This mini-review focused on the recent progress in application of poly-epsiloncaprolactone based materials for controlled release of cancer therapy drugs. A careful search was performed on web of science, mainly focused on the related papers published from 2013 to 2016. Conclusion: Recent advances in applying poly-epsilon-caprolactone for controlled delivery and targeting release of chemical anti-tumor drugs were summarized in this mini-review. Benefited from the efforts of scientists all over the world, various chemotherapeutic drug delivery systems based on different formulations of poly-epsilon-caprolactone related materials have been evaluated. It has been widely recognized that the introduction of of poly-epsilon-caprolactone components into drug delivery systems would increase drug loading capacity, decrease leakage, prolong releasing period and result in controllable releasing rate. Especially with the development of environment-responsive delivery systems (pH-, thermo-, magnetic field- and light-responsive drug carriers), enhanced tumor cell targeting potential, as well as decreased systemic toxicity would be realized.

Background: Colorectal cancer is a devastating disease with a dismal prognosis which is heavily hampered by delayed diagnosis. Surgical resection, radiation therapy and chemotherapy are the curative options. Due to few therapeutic treatments available i.e., mono and combination therapy and development of resistance towards drug response, novel and efficacious therapy are urgently needed. Objective: In this study, we have studied the potential of histone deacetylase inhibitors in colorectal cancer. Results: Histone deacetylase inhibitors (HDACIs) are an emerging class of therapeutic agents having potential anticancer activity with minimal toxicity for different types of malignancies in preclinical studies. HDACIs have proven less effective in monotherapy thus the combination of HDACIs with other anticancer agents are being assessed for the treatment of colorectal cancer. Conclusion: The molecular mechanism emphasizing the anticancer effect of HDACIs in colorectal cancer was illustrated and a recapitulation was carried out on the recent advances in the rationale behind combination therapies currently underway in clinical evaluations.

Background: Alternative splicing is one of the post transcriptional modifications through which multiple mRNA isoforms are produced from any gene, also known as splice variants. These are expressed in tissue and developmental stage specific manner that are important during the development. Most human genes undergo alternative splicing, thus contributing to the diversity of proteins. However, many abnormal splicing processes may result in human diseases. Non-steroidal antiinflammatory drugs (NSAIDs) are medications that act as analgesics, anti-pyretics and antiinflammatory by affecting Cox genes and their products. Usually NSAIDs cause gastrotoxicity however, isozyme-specific NSAIDs exhibit a comparatively reduced gastrotoxic effect. Such NSAIDs have a broader range of application particularly as chemo-preventive drugs. It is known that changes at the active site of an enzyme may illicit a diverse range of responses. Such changes might explain the underlying reason as to why patients appear to respond differently to different NSAIDs. Methods: An extensive literature search has been carried out using Pubmed and web of science databases considering the papers in last 10 years mainly on alternative splicing and NSAIDs. Conclusion: We have reviewed in detail the insight into the action of NSAIDs targeting specific isoforms of different genes. In future, the complete understanding of NSAIDs associated genes and their expression studies may be helpful in generating drugs with increased specificity.

Background: Brain cancer from metastasized breast cancer has a high mortality rate in women. The treatment of lesions is hampered in large part by the blood-brain barrier (BBB), which prevents adequate distribution of anti-cancer compounds to brain metastases. Method: In this study we used a novel screening method to identify candidate molecules that are well-suited to utilizing the BBB choline transporter for distribution into the brain parenchyma. Results: From our screen we identified two compounds, Ch-1 and Ch-2 that were able to reduce the brain tumor burden in a murine mouse model of brain metastasis of breast cancer. These compounds also significantly increased the survival of mice by more than 10 days. Mechanistic studies indicated that Ch-1 is able to prevent the activation of the pro-survival mitogen-activated kinases (MAPKs) by osteoactivin (OA; Glycoprotein nonmetastatic melanoma protein B GPNMB). Conclusion: The results from this study show that nutrient transporter virtual screening is a viable novel alternative to traditional drug screening programs to identify anti-cancer compounds for the treatment of brain cancers.

Background: Multidrug resistance in cancer (MDR) occurs when tumours become crossresistant to a range of different anticancer agents. One mechanism by which MDR can be acquired is through cell to cell communication pathways. Membrane-derived microparticles (MPs) are emerging as important signaling molecules in this process. MPs are released from most eukaryotic cells and transfer functional proteins and nucleic acids to recipient cells conferring deleterious traits within the cancer cell population including MDR, metastasis, and angiogenesis. MP formation is known to be dependent on calpain, an intracellular cysteine protease which acts to cleave the cytoskeleton underlying the plasma membrane, resulting in cellular surface blebbing Objective: To establish the role of calpain in vesiculation in malignant and non-malignant cells by 1) comparing membrane vesiculation at rest and following the release of intracellular calcium, and 2) comparing vesiculation in the presence and absence of calpain inhibitor II (ALLM). Method: This study examines the differences in vesiculation between malignant and non-malignant cells using high-resolution Atomic Force Microscopy (AFM). HBEC, MBE-F, MCF-7, and MCF- 7/Dx cells were analysed at rest and following treatment with calcium ionophore A23187 for 18 hours. Vesiculation of calcium activated and resting malignant and non-malignant cells was also assessed after 18 hour treatment of calpain inhibitor II (ALLM). Results: We demonstrate that malignant MCF-7 and MCF-7/Dx cells have an intrinsically higher degree of vesiculation at rest when compared to non-malignant human brain endothelial cells (HBEC) and human mammary epithelial cells (MBE-F). Cellular activation with the calcium ionophore A23187 resulted in an increase in vesiculation in all cell types. We show that calpain-mediated MP biogenesis is the dominant pathway at rest in malignant cells as vesiculation was shown to be inhibited with calpain inhibitor II (ALLM). Conclusion: These results suggest that differences in the biogenic pathways exist in malignant and non-malignant cells and have important implications in defining novel strategies to selectively target malignant cells for the circumvention of deleterious traits acquired through intercellular exchange of extracellular vesicles.