Current Cancer Drug Targets - Volume 21, Issue 2, 2021

Matrix metalloproteinases (MMPs) are a group of zinc-dependent metalloendopeptidases that are responsible for the degradation, repair, and remodeling of extracellular matrix components. MMPs play an important role in maintaining a normal physiological function and preventing diseases, such as cancer and cardiovascular diseases. Natural products derived from plants have been used as traditional medicine for centuries. Its active compounds, such as catechin, resveratrol and quercetin, are suggested to play an important role as MMPs inhibitors, thereby opening new insights into their applications in many fields, such as pharmaceutical, cosmetic, and food industries. This review summarises the current knowledge of plant-derived natural products with MMP-modulating activities. Most of the reviewed plant-derived products exhibit an inhibitory activity on MMPs. Amongst MMPs, MMP-2 and MMP-9 are the most studied. The expression of MMPs is inhibited through respective signaling pathways, such as MAPK, NF-ΚB and PI3 kinase pathways, which contribute to the reduction in cancer cell behaviors, such as proliferation and migration. Most studies have employed in vitro models, but a limited number of animal studies and clinical trials have been conducted. Even though plant-derived products show promising results in modulating MMPs, more in vivo studies and clinical trials are needed to support their therapeutic applications in the future.

The scenario of systemic therapy for prostate cancer is rapidly evolving, with new drugs and new treatment options. To update the background knowledge of shared uro-oncologic practice, we reviewed current statements and landmarks in systemic therapy. A number of new agents are under investigation in non-metastatic and metastatic disease. Similarly, new target imaging technologies are under development to improve the detection rate of true non-metastatic and true metastatic patient. Five new drugs have shown to be effective on progression-free and overall survival in metastatìc prostate cancer. However, the optimal sequencing of these treatments requires further investigation. The tolerability and side effects of the new drugs are also crucial issues to be discussed, as well as their activity against the disease. The uro-oncologic team has to stay updated about new medical therapies in order to be confident in debating with other professionals involved in prostate cancer decision making. Different points of view and nuances should be shared during multidisciplinary group discussions to achieve a balanced decision in disease management.

Tumor recurrence and drug resistance are two of the key factors affecting the prognosis of cancer patients. Cancer stem cells (CSCs) are a group of cells with infinite proliferation potential which are not sensitive to traditional therapies, including radio- and chemotherapy. These CSCs are considered to be central to tumor recurrence and the development of drug resistance. In addition, CSCs are important targets in cancer immunotherapy because of their expression of novel tumorassociated antigens, which result from mutations in cancer cells over the course of treatment. Emerging immunotherapies, including cancer vaccines, checkpoint blockade therapies, and transferred immune cell therapies, have all been shown to be more effective when they selectively target CSCs. Such therapies may also provide novel additions to the current therapeutic milieu and may offer new therapeutic combinations for treatment. This review summarizes the relationships between various immunotherapies and CSCs and provides novel insights into potential therapeutic applications for these approaches in the future.

MUC proteins have great significance as prognostic and diagnostic markers as well as a potential target for therapeutic interventions in most cancers of glandular epithelial origin. These are high molecular weight glycosylated proteins located in the epithelial lining of several tissues and ducts. Mucins belong to a heterogeneous group of large O-glycoproteins that can be either secreted or membrane-bound. Glycosylation, a post-translational modification affects the biophysical, functional and biochemical properties and provides structural complexity for these proteins. Aberrant expression and glycosylation of mucins contribute to tumour survival and proliferation in many cancers, which in turn activates numerous signalling pathways such as NF-kB, ERα, HIF, MAPK, p53, c-Src, Wnt and JAK-STAT, etc. This subsequently induces cancer cell growth, proliferation and metastasis. The present review mainly demonstrates the functional aspects of MUC glycoproteins along with its unique signalling mechanism and role of aberrant glycosylation in cancer progression and therapeutics. The importance of MUC proteins and its subtypes in a wide spectrum of cancers including but not limited to breast cancer, colorectal cancer, endometrial and cervical cancer, lung cancer, primary liver cancer, pancreatic cancer, prostate cancer and ovarian cancer has been exemplified with significance in targeting the same. Several patents associated with the MUC proteins in the field of cancer therapy are also emphasized in the current review.

Triple-negative breast cancer presents an aggressive form of breast cancer subtype, which further lacks efficient treatment strategies and prognostic markers. Genomic heterogeneity in TNBC has led to the relapse of tumor and cancer stem cells with a higher likelihood of distal metastasis. Several studies supported the notion that miRNAs may act as oncogene or tumor suppressors in TNBC. miRNAs may function as a global regulator of TNBC by targeting post-transcriptional regulation of several genes involved in influencing metastatic events, but the exact mechanism involved in inducing the effect is yet to be elucidated. In this review, we summarized miRNA expression, which can functionally suppress metastatic cascade in TNBC by targeting epithelial to mesenchymal transition, metastatic colonization, cancer stem cells, invasion, migration and metastasis. miRNAs may appear as a metastatic biomarker to predict distal reoccurrence of TNBC in lungs, brain and lymph nodes. miRNA can act as a prognostic marker in metastatic TNBC, thereby predicting overall survival, disease-free survival and distant metastasis-free survival in affected patients. The present review article is an attempt to gain an insight into the repertoire of miRNA that may emerge out as an effective treatment strategy, novel biomarker of distal reoccurrence and prognostic marker in metastatic TNBC.

Background: The prevalence of breast cancer is increasing at an alarming rate and thus demands exploration of the most relevant diagnostic biomarkers. RAD50 is a cancer susceptibility gene that encodes a DNA damage repairing protein. Its role in breast cancer as clinico-pathological specific biomarker has yet to be explored. Objective: This study was aimed to investigate the RAD50 expression and its promoter’s methylation level variations in breast invasive carcinoma patients having different clinico-pathological features. This study further explored the mutational spectrum of RAD50 and the correlation of its expression with the survival of patients and the effectiveness of drugs used for treatment. Methods: Enrichment analysis of RAD50 was accomplished using the platform of GeneCards. The information regarding RAD50 expression, its promoter methylation and impact on survival of patient was retrieved from TCGA and CPTAC databases. However, the effect of RAD50 expression on tumor’s response to various drugs was deduced through the analysis of CCLE and genomic of GDSC dataset. Results: The promoter hyper-methylation and elevated expression of RAD50 was documented in various subgroups of breast invasive carcinoma. The subjects having low/medium expression levels were observed to survive longer than patients exhibiting high expression of RAD50 except for post-menopausal subjects. The frequency of missense mutations was higher in RAD50 than truncating mutations. Most of the drugs were found to have a positive correlation with RAD50 expression. Conclusion: The status of RAD50 promoter’s methylation inversely correlates with the expression level of RAD50. While RAD50 is overexpressed in breast cancer patients and thus makes tumor resistant against many anti-cancer drugs.