Synthesis and biological evaluation of a novel anticancer agent CBISC that induces DNA damage response and diminishes levels of mutant-p53

Conor T Ronayne; Sravan K Jonnalagadda; Shirisha Jonnalagadda; Grady L Nelson; Lucas N Solano; Hithardha Palle; Chinnadurai Mani; Jon Rumbley; Jon Holy; Venkatram R Mereddy

doi:10.1016/j.bbrc.2021.05.062

Synthesis and biological evaluation of a novel anticancer agent CBISC that induces DNA damage response and diminishes levels of mutant-p53

Biochem Biophys Res Commun. 2021 Jul 12:562:127-132. doi: 10.1016/j.bbrc.2021.05.062. Epub 2021 May 26.

Affiliations

¹ Integrated Biosciences Graduate Program, University of Minnesota, Duluth, MN, 55812, USA.
² Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX, 79430, USA.
³ Department of Pharmacy Practice & Pharmaceutical Sciences, University of Minnesota, Duluth, MN, 55812, USA.
⁴ Department of Biomedical Sciences, University of Minnesota Medical School, Duluth, MN, 55812, USA.
⁵ Integrated Biosciences Graduate Program, University of Minnesota, Duluth, MN, 55812, USA; Department of Pharmacy Practice & Pharmaceutical Sciences, University of Minnesota, Duluth, MN, 55812, USA; Department of Chemistry and Biochemistry, University of Minnesota Duluth, Duluth, MN, 55812, USA. Electronic address: vmereddy@d.umn.edu.

PMID: 34051576
DOI: 10.1016/j.bbrc.2021.05.062

Abstract

A novel nitrogen mustard CBISC has been synthesized and evaluated as an anticancer agent. CBISC has been shown to exhibit enhanced cell proliferation inhibition properties against mutant p53 cell lines colorectal cancer WiDr, pancreatic cancer (MIAPaCa-2 and PANC-1), and triple negative breast cancer (MDA-MB-231 and MDA-MB-468). In vitro mechanism of action studies revealed perturbations in the p53 pathway and increased cell death as evidenced by western blotting, immunofluorescent microscopy and MTT assay. Further, in vivo studies revealed that CBISC is well tolerated in healthy mice and exhibited significant in vivo tumor growth inhibition properties in WiDr and MIAPaCa-2 xenograft models. These studies illustrate the potential utility of CBISC as an anticancer agent.

Keywords: Alkylating agent; Apoptosis; DNA-damage; MIAPaCa-2; Mutant p53; WiDr.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis*
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
CRISPR-Cas Systems / genetics
Cell Line, Tumor
Cell Proliferation / drug effects
Chlorambucil / chemistry
Chlorambucil / pharmacology
Chloramphenicol / chemistry
Chloramphenicol / pharmacology
DNA Damage*
Female
Mice
Mice, Nude
Mutant Proteins / metabolism*
Poly(ADP-ribose) Polymerases / metabolism
Tumor Suppressor Protein p53 / genetics*
Tumor Suppressor Protein p53 / metabolism
Xenograft Model Antitumor Assays

Substances

Antineoplastic Agents
Mutant Proteins
Tumor Suppressor Protein p53
Chlorambucil
Chloramphenicol
Poly(ADP-ribose) Polymerases