Biochemical pharmacology of adenylyl cyclases in cancer.

Globally, despite extensive research and pharmacological advancement, cancer remains one of the most common causes of mortality. Understanding the signaling pathways involved in cancer progression is essential for the discovery of new drug targets. The adenylyl cyclase (AC) superfamily comprises glycoproteins that regulate intracellular signaling and convert ATP into cyclic AMP, an important second messenger. The present review highlights the involvement of ACs in cancer progression and suppression, broken down for each specific mammalian AC isoform. The precise mechanisms by which ACs contribute to cancer cell proliferation and invasion are not well understood and are variable among cancer types; however, AC overactivation, along with that of downstream regulators, presents a potential target for novel anticancer therapies. The expression patterns of ACs in numerous cancers are discussed. In addition, we highlight inhibitors of AC-related signaling that are currently under investigation, with a focus on possible anti-cancer strategies. Recent discoveries with small molecules regarding more direct modulation AC activity are also discussed in detail. A more comprehensive understanding of different components in AC-related signaling could potentially lead to the development of novel therapeutic strategies for personalized oncology and might enhance the efficacy of chemoimmunotherapy in the treatment of various cancers.

Screening of the Prime bioactive compounds from Aloe vera as potential anti-proliferative agents targeting DNA.

BACKGROUND: Aloe vera extract and its bioactive compounds possess anti-proliferative properties against cancer cells. However, no detailed molecular mechanism of action studies has been reported. We have now employed a computational approach to scrutinize the molecular mechanism of lead bioactive compounds from Aloe vera that potentially inhibit DNA synthesis. METHODS: Initially, the anti-proliferative activity of Aloe vera extract was examined in human breast cancer cells (in vitro/in vivo). Later on, computational screening of bioactive compounds from Aloe vera targeting DNA was performed by molecular docking and molecular dynamics simulation. RESULTS: In-vitro and in-vivo studies confirm that Aloe vera extract effectively suppresses the growth of breast cancer cells without significant cytotoxicity towards non-cancerous normal immortal cells. Computational screening predicts that growth suppression may be due to the presence of DNA intercalating bioactive compounds (riboflavin, daidzin, aloin, etc.) contained in Aloe vera. MM/PBSA calculation showed that riboflavin has a higher binding affinity at the DNA binding sites compared to standard drug daunorubicin. CONCLUSIONS: These observations support the hypothesis that riboflavin may be exploited as an anti-proliferative DNA intercalating agent to prevent cancer and is worthy of testing for the management of cancer by performing more extensive pre-clinical and if validated clinical trials.

The transformation of cancer-associated fibroblasts: Current perspectives on the role of TGF-ß in CAF mediated tumor progression and therapeutic resistance.

Over the last few years, the Transforming growth factor- ß (TGF-ß) has been significantly considered as an effective and ubiquitous mediator of cell growth. The cytokine, TGF-ß is being increasingly recognized as the most potent inducer of cancer cell initiation, differentiation, migration as well as progression through both the SMAD-dependent and independent pathways. There is growing evidence that supports the role of secretory cytokine TGF-ß as a crucial mediator of tumor-stroma crosstalk. Contextually, the CAFs are the prominent component of tumor stroma that helps in tumor progression and onset of chemoresistance. The interplay between the CAFs and the tumor cells through the paracrine signals is facilitated by cytokine TGF-ß to induce the malignant progression. Here in this review, we have dissected the most recent advancements in understanding the mechanisms of TGF-ß induced CAF activation, their multiple origins, and most importantly their role in conferring chemoresistance. Considering the pivotal role of TGF-ß in tumor perogression and associated stemness, it is one the proven clinical targets We have also included the clinical trials going on, targeting the TGF-ß and CAFs crosstalk with the tumor cells. Ultimately, we have underscored some of the outstanding issues that must be deciphered with utmost importance to unravel the successful strategies of anti-cancer therapies.

Paracrine TGF-ß1 from breast cancer contributes to chemoresistance in cancer associated fibroblasts via upregulation of the p44/42 MAPK signaling pathway.

Conventionally, Cancer-associated fibroblasts (CAFs) are considered as an inducer of chemoresistance in cancer cells. However, the underlying mechanism by which carcinomas induce chemoresistance in CAFs through tumor-stroma cross-talk is largely unknown. Henceforth, we uncovered a network of paracrine signals between carcinoma and CAFs that drives chemoresistance in CAFs. Acquired tamoxifen and 5-Fu resistant cell lines MCF-7 and MDA-MB-468 respectively showed higher apoptotic resistance compared to the parental cell. Besides, chemoresistant breast cancer cells showed overexpression of TGF-ß1 and have the higher potential to induce CAF phenotype in the normal dermal fibroblasts in a paracrine manner through the TGF-ß1 cytokine, compared to their parental cell. Moreover, the chemoresistant cancer cells augmented the EMT markers with a reduction of E-cadherin in the CAFs. Importantly we found out that the TGF- ß1 enriched conditioned media from both of the resistant cells triggered chemoresistance in the CAFs by p44/42 MAPK signaling axis. Mechanistically, pharmacological and genetic blockade of TGF-ß1 inhibits p44/42 MAPK activation with the subsequent restoration of chemosensitivity in the CAFs. Altogether we ascertained that chemoresistant cancer cells have tremendous potential to modulate the CAFs compared to the parental counterpart. Targeting TGF-ß1 and p44/42 MAPK signaling in the future may help to abrogate the chemoresistance in the CAFs.