ASR490, a Small Molecule, Overrides Aberrant Expression of in Colorectal Cancer

Overview

Journal Mol Cancer Ther

Date 2020 Oct 22

PMID 33087513

Citations 3

Authors

Ashish Tyagi

Balaji Chandrasekaran

Venkatesh Kolluru

Becca V Baby

Cibi A Sripathi

Murali K Ankem

Srinivasa R Ramisetti

Venkat R Chirasani

Nikolay V Dokholyan

Arun K Sharma

Chendil Damodaran

Affiliations

Soon will be listed here.

Abstract

activation triggers significant oncogenic signaling that manifests as enhanced metastatic potential and tumorigenesis in colorectal cancer. Novel small-molecule inhibitors, mainly plant-derived analogs, have low toxicity profiles and higher bioavailability. In this study, we have developed a small molecule, ASR490, by modifying structure of naturally occurring compound Withaferin A. ASR490 showed a growth-inhibitory potential by downregulating signaling in HCT116 and SW620 cell lines. Docking studies and thermal shift assays confirmed that ASR490 binds to , whereas no changes in and expression were seen in colorectal cancer cells. governs epithelial-to-mesenchymal transition signaling and is responsible for metastasis, which was abolished by ASR490 treatment. To further confirm the therapeutic potential of ASR490, we stably overexpressed in HCT-116 cells and determined its inhibitory potential in transfected colorectal cancer (Notch1/HCT116) cells. ASR490 effectively prevented cell growth in both the vector ( = 0.005) and ( = 0.05) transfectants. The downregulation of signaling was evident, which corresponded with downregulation of mesenchymal markers, including and and induction of in HCT-116 transfectants. Intraperitoneal administration of a 1% MTD dose of ASR490 (5 mg/kg) effectively suppressed the tumor growth in control (pCMV/HCT116) and Notch1/HCT116 in xenotransplanted mice. In addition, downregulation of and survival signaling in ASR-treated tumors confirmed the results. In conclusion, ASR490 appears to be a potent agent that can inhibit signaling in colorectal cancer.

Citing Articles

Withaferin A: A Dietary Supplement with Promising Potential as an Anti-Tumor Therapeutic for Cancer Treatment - Pharmacology and Mechanisms.

Xing Z, Su A, Mi L, Zhang Y, He T, Qiu Y Drug Des Devel Ther. 2023; 17:2909-2929.

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A small molecule inhibitor of Notch1 modulates stemness and suppresses breast cancer cell growth.

Saran U, Chandrasekaran B, Tyagi A, Shukla V, Singh A, Sharma A Front Pharmacol. 2023; 14:1150774.

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Recent Advances in the Chemistry and Therapeutic Evaluation of Naturally Occurring and Synthetic Withanolides.

Singh A, Raza A, Amin S, Damodaran C, Sharma A Molecules. 2022; 27(3).

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