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Journal of Pharmacology and Experimental Therapeutics

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Research ArticleDrug Discovery and Translational Medicine

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

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 and Michael A Ihnat
Journal of Pharmacology and Experimental Therapeutics February 26, 2015, jpet.114.220335; DOI: https://doi.org/10.1124/jpet.114.220335
Anja Bastian
1 Univ Oklahoma Health Sciences Center;
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Jessica E Thorpe
1 Univ Oklahoma Health Sciences Center;
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Bryan C Disch
2 DormaTarg Inc;
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Lora C Bailey-Downs
3 DormaTarg;
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Aleem Gangjee
4 Duquesne University;
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Ravi K. V. Devambatla
4 Duquesne University;
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Jim Henthorn
1 Univ Oklahoma Health Sciences Center;
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Kenneth M Humphries
5 Oklahoma Medical Research Foundation
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Shraddha S Vadvalkar
5 Oklahoma Medical Research Foundation
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Michael A Ihnat
1 Univ Oklahoma Health Sciences Center;
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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. 5-[(4-Methylphenyl)thio]-9H-pyrimido[4,5-b]indole-2,4-diamine (AG311), 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 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, 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.

  • anticancer agents
  • breast cancer
  • cell death
  • mitochondria
  • necrosis
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 384 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 384, Issue 2
1 Feb 2023
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Research ArticleDrug Discovery and Translational Medicine

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

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 and Michael A Ihnat
Journal of Pharmacology and Experimental Therapeutics February 26, 2015, jpet.114.220335; DOI: https://doi.org/10.1124/jpet.114.220335

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Research ArticleDrug Discovery and Translational Medicine

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

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 and Michael A Ihnat
Journal of Pharmacology and Experimental Therapeutics February 26, 2015, jpet.114.220335; DOI: https://doi.org/10.1124/jpet.114.220335
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