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Molecular Cancer Therapeutics
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Small Molecule Therapeutics

ASR490, a Small Molecule, Overrides Aberrant Expression of Notch1 in Colorectal Cancer

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 and Chendil Damodaran
Ashish Tyagi
1Department of Urology, University of Louisville, Louisville, Kentucky.
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Balaji Chandrasekaran
1Department of Urology, University of Louisville, Louisville, Kentucky.
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Venkatesh Kolluru
1Department of Urology, University of Louisville, Louisville, Kentucky.
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Becca V. Baby
1Department of Urology, University of Louisville, Louisville, Kentucky.
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Cibi A. Sripathi
1Department of Urology, University of Louisville, Louisville, Kentucky.
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Murali K. Ankem
1Department of Urology, University of Louisville, Louisville, Kentucky.
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Srinivasa R. Ramisetti
2Department of Pharmacology, Penn State Cancer Institute, Penn State College of Medicine, Hershey, Pennsylvania.
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Venkat R. Chirasani
2Department of Pharmacology, Penn State Cancer Institute, Penn State College of Medicine, Hershey, Pennsylvania.
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Nikolay V. Dokholyan
3Department of Pharmacology, Biochemistry and Molecular Biology, Penn State College of Medicine, Hershey, Pennsylvania.
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Arun K. Sharma
2Department of Pharmacology, Penn State Cancer Institute, Penn State College of Medicine, Hershey, Pennsylvania.
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Chendil Damodaran
1Department of Urology, University of Louisville, Louisville, Kentucky.
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  • For correspondence: chendil.damodaran@louisville.edu
DOI: 10.1158/1535-7163.MCT-19-0949 Published December 2020
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Abstract

Notch1 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 Notch1 signaling in HCT116 and SW620 cell lines. Docking studies and thermal shift assays confirmed that ASR490 binds to Notch1, whereas no changes in Notch2 and Notch3 expression were seen in colorectal cancer cells. Notch1 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 Notch1 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 (P = 0.005) and Notch1 (P = 0.05) transfectants. The downregulation of Notch1 signaling was evident, which corresponded with downregulation of mesenchymal markers, including N-cadherin and β-catenin and induction of E-cadherin 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 Notch1 and survival signaling in ASR-treated tumors confirmed the in vitro results. In conclusion, ASR490 appears to be a potent agent that can inhibit Notch1 signaling in colorectal cancer.

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

  • Mol Cancer Ther 2020;19:2422–31

  • Received October 10, 2019.
  • Revision received May 14, 2020.
  • Accepted October 5, 2020.
  • Published first October 21, 2020.
  • ©2020 American Association for Cancer Research.
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Molecular Cancer Therapeutics: 19 (12)
December 2020
Volume 19, Issue 12
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ASR490, a Small Molecule, Overrides Aberrant Expression of Notch1 in Colorectal Cancer
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 and Chendil Damodaran
Mol Cancer Ther December 1 2020 (19) (12) 2422-2431; DOI: 10.1158/1535-7163.MCT-19-0949

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ASR490, a Small Molecule, Overrides Aberrant Expression of Notch1 in Colorectal Cancer
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 and Chendil Damodaran
Mol Cancer Ther December 1 2020 (19) (12) 2422-2431; DOI: 10.1158/1535-7163.MCT-19-0949
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