2. Academic Validation
  3. Enhanced cytotoxicity of a novel family of ATPase inhibitors in colorectal cancer cells with high NAT2 activity

Enhanced cytotoxicity of a novel family of ATPase inhibitors in colorectal cancer cells with high NAT2 activity

  • Biochem Pharmacol. 2022 Sep;203:115184. doi: 10.1016/j.bcp.2022.115184.
Xiaonan Zhang 1,  Ece Akcan 1,  Mario Correia 2,  Natallia Rameika 1,  Snehangshu Kundu 1,  Ivaylo Stoimenov 1,  Veronica Rendo 3,  Anna U Eriksson 4,  Martin Haraldsson 5,  Daniel Globisch 2,  Tobias Sjöblom 6
Affiliations

Affiliations

  • 1 Department of Immunology, Genetics and Pathology, Uppsala University, SE-751 85 Uppsala, Sweden.
  • 2 Department of Chemistry, BMC, Science for Life Laboratory, Uppsala University, SE-751 24 Uppsala, Sweden.
  • 3 Department of Immunology, Genetics and Pathology, Uppsala University, SE-751 85 Uppsala, Sweden; Department of Cancer Biology, Dana Farber Cancer Institute, Boston, MA, 02215, USA.
  • 4 Department of Chemistry, CBCS, KBC-C4, Umeå University, SE-901 87 UMEÅ, Sweden.
  • 5 Chemical Biology Consortium Sweden (CBCS), Science for Life Laboratory, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
  • 6 Department of Immunology, Genetics and Pathology, Uppsala University, SE-751 85 Uppsala, Sweden. Electronic address: [email protected].
PMID: 35872325 DOI: 10.1016/j.bcp.2022.115184
Abstract

Loss of heterozygosity (LOH) is a hallmark feature of Cancer genomes that reduces allelic variation, thereby creating tumor specific vulnerabilities which could be exploited for therapeutic purposes. We previously reported that loss of drug metabolic arylamine N-acetyltransferase 2 (NAT2) activity following LOH at 8p22 could be targeted for collateral lethality Anticancer therapy in colorectal Cancer (CRC). Here, we report a novel compound CBK034026C that exhibits specific toxicity towards CRC cells with high NAT2 activity. Connectivity Map analysis revealed that CBK034026C elicited a response pattern related to ATPase inhibitors. Similar to ouabain, a potent inhibitor of the Na+/K+-ATPase, CBK034026C activated the Nf-kB pathway. Further metabolomic profiling revealed downregulation of pathways associated with antioxidant defense and Mitochondrial Metabolism in CRC cells with high NAT2 activity, thereby weakening the protective response to oxidative stress induced by CBK034026C. The identification of a small molecule targeting metabolic vulnerabilities caused by NAT2 activity provides novel avenues for development of Anticancer agents.

Keywords

ATPase inhibitors; Arylamine N acetyltransferase 2 (NAT2); Colorectal cancer; Loss of heterozygosity (LOH); Nf-kB pathway; Small molecule therapeutics.

Figures
Products