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Experimental and Molecular Therapeutics

Abstract 3776: Mechanistic evaluation of AG311 - an OXPHOS inhibitor - as a potential treatment for breast cancer

Anja Bastian, Satoshi Matsuzaki, Kenneth M. Humphries, Lora C. Bailey-Downs, Aleem Gangjee and Michael A. Ihnat
Anja Bastian
Univ. of Oklahoma Health Sciences Center, Oklahoma City, OK;
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Satoshi Matsuzaki
Oklahoma Medical Research Foundation, Oklahoma City, OK;
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Kenneth M. Humphries
Oklahoma Medical Research Foundation, Oklahoma City, OK;
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Lora C. Bailey-Downs
Univ. of Oklahoma Health Sciences Center, Oklahoma City, OK;
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Aleem Gangjee
Duquesne University, Pittsburgh, PA.
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Michael A. Ihnat
Univ. of Oklahoma Health Sciences Center, Oklahoma City, OK;
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DOI: 10.1158/1538-7445.AM2016-3776 Published July 2016
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Proceedings: AACR 107th Annual Meeting 2016; April 16-20, 2016; New Orleans, LA

Abstract

About fifty percent of breast cancer patients receiving a combination of surgery, radiation and systemic therapy will not remain cancer-free. Most solid tumors, including breast tumors, have hypoxic regions that can contribute to chemoresistance, radioresistance, and poor differentiation in tumors resulting in a poor clinical outcome in patients with advanced disease. It has been reported that mitochondrial respiration remains active in these hypoxic microenvironments. Complex I of the mitochondrial electron transport chain (ETC) has been shown to switch to a de-active catalytic state under hypoxic conditions. The purpose of this study was to investigate the potential anticancer action of a novel compound with antimitochondrial activity under hypoxic conditions. AG311 (5-[(4-Methylphenyl)thio]-9H-pyrimido[4,5-b]indole-2,4-diamine) is a small molecular weight compound shown to inhibit complex I activity in vitro and to drastically reduce mitochondrial oxygen consumption rate by 62.9% at 7.5 μM in breast cancer cells (p<0.001). In two triple negative breast cancer mouse models (MDA-MB-435 and 4T1), AG311 significantly reduced tumor volume by 85% and 81%, respectively (p<0.001 for both). In this current study, the effect of the microenvironment on AG311 mitochondrial inhibition was examined. First, it was shown that AG311 inhibited complex I activity not only in vitro, but also in breast cancer cells (54% inhibition, p<0.001) and tumor homogenate (50% inhibition, p = 0.01). AG311 induced greater cytotoxicity in cells (MDA-MB-435) cultured in glucose-depleted media (IC50 15.5 μM vs 20.0 μM, p<0.01), a condition favoring mitochondrial ATP production, as compared to normal glucose concentrations. Further, co-treatment of AG311 with dichloroacetate, a pyruvate dehydrogenase kinase inhibitor and stimulator of oxidative phosphorylation, showed a synergistic effect on cell kill (CI = 0.7 at 20 μM). Importantly, hypoxic conditions (1% O2) significantly sensitized cancer cells to AG311-induced cell death (from 43.3% to 30.1%, p = 0.019). Further, the effect of AG311 on the deactive form of complex I, which is promoted under hypoxic conditions was assessed by measuring NADH oxidation rate. The switch to the de-active state was thermally-induced in mitochondrial homogenates and once in this state, complex I activity was sensitized to AG311 inhibition (from 45.4% to 65.0% inhibition, p = 0.04). Thus, a mitochondrial inhibitor that preferentially inhibits the de-active state of complex I in hypoxic tumor regions could potentially provide a therapeutic benefit.

Citation Format: Anja Bastian, Satoshi Matsuzaki, Kenneth M. Humphries, Lora C. Bailey-Downs, Aleem Gangjee, Michael A. Ihnat. Mechanistic evaluation of AG311 - an OXPHOS inhibitor - as a potential treatment for breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3776.

  • ©2016 American Association for Cancer Research.
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Cancer Research: 76 (14 Supplement)
July 2016
Volume 76, Issue 14 Supplement
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Abstract 3776: Mechanistic evaluation of AG311 - an OXPHOS inhibitor - as a potential treatment for breast cancer
Anja Bastian, Satoshi Matsuzaki, Kenneth M. Humphries, Lora C. Bailey-Downs, Aleem Gangjee and Michael A. Ihnat
Cancer Res July 15 2016 (76) (14 Supplement) 3776; DOI: 10.1158/1538-7445.AM2016-3776

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Abstract 3776: Mechanistic evaluation of AG311 - an OXPHOS inhibitor - as a potential treatment for breast cancer
Anja Bastian, Satoshi Matsuzaki, Kenneth M. Humphries, Lora C. Bailey-Downs, Aleem Gangjee and Michael A. Ihnat
Cancer Res July 15 2016 (76) (14 Supplement) 3776; DOI: 10.1158/1538-7445.AM2016-3776
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