A small molecule with anticancer and antimetastatic activities induces rapid mitochondrial-associated necrosis in breast cancer.

Abstract

Therapy for treatment-resistant breast cancer provides limited options and the response rates are low. Therefore, the development of therapies with alternative chemotherapeutic strategies is necessary. AG311 (5-[(4-methylphenyl)thio]-9H-pyrimido[4,5-b]indole-2,4-diamine), a small molecule, is being investigated in preclinical and mechanistic studies for treatment of resistant breast cancer through necrosis, an alternative cell death mechanism. In vitro, AG311 induces rapid necrosis in numerous cancer cell lines as evidenced by loss of membrane integrity, ATP depletion, HMGB1 (high-mobility group protein B1) translocation, nuclear swelling, and stable membrane blebbing in breast cancer cells. Within minutes, exposure to AG311 also results in mitochondrial depolarization, superoxide production, and increased intracellular calcium levels. Additionally, upregulation of mitochondrial oxidative phosphorylation results in sensitization to AG311. This AG311-induced cell death can be partially prevented by treatment with the mitochondrial calcium uniporter inhibitor, Ru360 [(μ)[(HCO2)(NH3)4Ru]2OCl3], or an antioxidant, lipoic acid. Additionally, AG311 does not increase apoptotic markers such as cleavage of poly (ADP-ribose) polymerase (PARP) or caspase-3 and -7 activity. Importantly, in vivo studies in two orthotopic breast cancer mouse models (xenograft and allograft) demonstrate that AG311 retards tumor growth and reduces lung metastases better than clinically used agents and has no gross or histopathological toxicity. Together, these data suggest that AG311 is a first-in-class antitumor and antimetastatic agent inducing necrosis in breast cancer tumors, likely through the mitochondria.

• Authors: Anja Bastian, Jessica E Thorpe, Bryan C Disch, Lora C Bailey-Downs, Aleem Gangjee, Ravi K V Devambatla, Jim Henthorn, Kenneth M Humphries, Shraddha S Vadvalkar, Michael A Ihnat
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 353 Issue 2 Pg. 392-404 (May 2015) ISSN: 1521-0103 [Electronic] United States
• PMID: 25720766 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

Chemical References

• 5-((4-methylphenyl)thio)-9H-pyrimido(4,5-b)indole-2,4-diamine
• Antineoplastic Agents
• Indoles
• Pyrimidines
• Superoxides
• Calcium

Topics

• Animals
• Antineoplastic Agents (pharmacology, toxicity)
• Apoptosis (drug effects)
• Calcium (metabolism)
• Cell Line, Tumor
• Cell Membrane Permeability (drug effects)
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Female
• Homeostasis (drug effects)
• Humans
• Indoles (pharmacology, toxicity)
• Male
• Membrane Potential, Mitochondrial (drug effects)
• Mice
• Mitochondria (drug effects, metabolism)
• Necrosis (chemically induced)
• Neoplasm Metastasis
• Pyrimidines (pharmacology, toxicity)
• Rats
• Superoxides (metabolism)
• Time Factors
• Triple Negative Breast Neoplasms (pathology)
• Xenograft Model Antitumor Assays