Cancer chemopreventive role of fisetin: Regulation of cell signaling pathways in different cancers.

It is becoming progressively more understandable that pharmaceutical targeting of drug-resistant cancers is challenging because of intra- and inter-tumor heterogeneity. Interestingly, naturally derived bioactive compounds have unique ability to modulate wide-ranging deregulated oncogenic cell signaling pathways. In this review, we have focused on the available evidence related to regulation of PI3K/AKT/mTOR, Wnt/ß-catenin, NF-κB and TRAIL/TRAIL-R by fisetin in different cancers. Fisetin has also been shown to inhibit the metastatic spread of cancer cells in tumor-bearing mice. We have also summarized how fisetin regulated autophagy in different cancers. In addition, this review also covers fisetin-mediated regulation of VEGF/VEGFR, EGFR, necroptosis and Hippo pathway. Fisetin has entered into clinical trials particularly in context of COVID19-associated inflammations. Furthermore, fisetin mediated effects are also being tested in clinical trials with reference to osteoarthritis and senescence. These developments will surely pave the way for full-fledge and well-designed clinical trials of fisetin in different cancers. However, we still have to comprehensively analyze and fully unlock pharmacological potential of fisetin against different oncogenic signaling cascades and non-coding RNAs. Fisetin has remarkable potential as chemopreventive agent and future studies must converge on the identification of additional regulatory roles of fisetin for inhibition and prevention of cancers.

The effect of antioxidants in Ehrlich Ascites Cancer.

A fundamental goal in molecular oncology is to unravel the underlying mechanisms which cause the cell transformation. In line with this approach, genome-wide functional screening approaches have revealed exciting insights into heterogeneous nature of cancer. Rapidly expanding horizons of research have unraveled myriad of pathways which play instrumental role in carcinogenesis and metastasis. Oxidative stress has also been reported to be significantly involved in cancer onset and progression. In line with this approach, oxidative stress modulating chemicals have always been sharply divided into antioxidants and oxidative stress-inducing agents. Conceptual and experimental advancements have enabled us to critically analyze full potential of these two different groups of chemicals in cancer chemoprevention. Different antioxidants are currently being analyzed in different phases of clinical trials. Although it has been reported in the literature that antioxidant supplements reduce tumor cells in some tumors or cause volume reduction in solid tumor sizes, there is no definite consensus. Therefore, an antioxidant supplement guideline based on more detailed clinical research and as a result of these is needed to achieve the best care for cancer patients and to avoid risky treatments for cancer patients.

TRAIL mediated signaling as a double-edged sword in pancreatic cancer: Analysis of brighter and darker sides of the pathway.

Genetic, genomic and proteomic studies have refined our concepts related to underlying mechanisms of pancreatic cancer. Increasingly sophisticated knowledge has started to shed light on the fact that pancreatic cancer harbored multiple epigenetic and genetic alterations and revealed complicated and dense tumor microenvironments. Our rapidly evolving knowledge about pancreatic cancer has helped us in identification of myriad of underlying mechanisms which play instrumental role in disease onset, drug resistance and epithelial to mesenchymal transition (EMT). Additionally, loss of apoptosis is the cornerstone of cancer biology and researchers have devoted considerable attention to the versatile regulators involved in loss and restoration of apoptosis. Discovery of TNF/TNFR, FasL/Fas and TRAIL/TRAIL-R opened new horizons for detailed analysis of intracellular mechanisms regulated by these pro-apoptotic molecules. Decades of cutting-edge research helped in translation of TRAIL-based therapeutics into clinically effective therapeutics. In this review, we will focus specifically on groundbreaking achievements which have leveraged our concepts related to TRAIL-mediated signaling to yet another level. We will also discuss how basic and clinical scientists are making efforts to overcome the stumbling blocks associated with efficacy of TRAIL-based therapeutics against TRAIL-resistant pancreatic cancers. We partition this multi-component review into overview of the conceptual breakthroughs in regulation of TRAIL-mediated signaling in pancreatic cancers, push and pull between pro- and anti-apoptotic proteins to regulate TRAIL-mediated apoptosis and how researchers have identified different natural and synthetic molecules to restore apoptosis in TRAIL-resistant pancreatic cancer. We have also summarized how long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) regulated TRAIL-mediated apoptosis in pancreatic cancer. More importantly we will also set spotlight on the darker side of TRAIL/TRAIL-R pathway in pancreatic cancer. Circumstantial evidence highlighted cancer promoting role of TRAIL/TRAIL-R in pancreatic cancer. These diametrically opposed context-dependent roles of TRAIL-pathway are intriguing and need comprehensive research to address outstanding questions.

Regulation of ROCK1/2 by long non-coding RNAs and circular RNAs in different cancer types.

Recent breakthroughs in high-throughput technologies have enabled the development of a better understanding of the functionalities of rho-associated protein kinases (ROCKs) under various physiological and pathological conditions. Since their discovery in the late 1990s, ROCKs have attracted the attention of interdisciplinary researchers due to their ability to pleiotropically modulate a myriad of cellular mechanisms. A rapidly growing number of published studies have started to shed light on the mechanisms underlying the regulation of ROCK1 and ROCK2 via long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) in different types of cancer. Detailed analyses have suggested that lncRNAs may be characteristically divided into oncogenic and tumor suppressor lncRNAs. Several exciting recent discoveries have also indicated how different lncRNAs and circRNAs modulate ROCK1/2 and mediate multistep cancer onset and progression. The present review chronicles the major advances that have been made in our understanding of the regulatory role of ROCK1/2 in different types of cancer, and how wide-ranging lncRNAs and circRNAs potentiate ROCK-driven signaling by blocking the targeting activities of tumor suppressor microRNAs.