RT Journal Article
SR Electronic
T1 A Small Molecule with Anticancer and Antimetastatic Activities Induces Rapid Mitochondrial-Associated Necrosis in Breast Cancer
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 392
OP 404
DO 10.1124/jpet.114.220335
VO 353
IS 2
A1 Anja Bastian
A1 Jessica E. Thorpe
A1 Bryan C. Disch
A1 Lora C. Bailey-Downs
A1 Aleem Gangjee
A1 Ravi K. V. Devambatla
A1 Jim Henthorn
A1 Kenneth M. Humphries
A1 Shraddha S. Vadvalkar
A1 Michael A. Ihnat
YR 2015
UL http://jpet.aspetjournals.org/content/353/2/392.abstract
AB 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.