Pyruvate Induces Transient Tumor Hypoxia by Enhancing Mitochondrial Oxygen Consumption and Potentiates the Anti-Tumor Effect of a Hypoxia-Activated Prodrug TH-302
- Takakusagi Yoichi
- Matsumoto Shingo
- Saito Keita
- Matsuo Masayuki
- Kishimoto Shun
- Wojtkowiak Jonathan W.
- DeGraff William
- Kesarwala Aparna H.
- Choudhuri Rajani
- Devasahayam Nallathamby
- Subramanian Sankaran
- Munasinghe Jeeva P.
- Gillies Robert J.
- Mitchell James B.
- Hart Charles P.
- Krishna Murali C.
DOIAbstract
TH-302 is a hypoxia-activated prodrug (HAP) of bromo isophosphoramide mustard that is selectively activated within hypoxic regions in solid tumors. Our recent study showed that intravenously administered bolus pyruvate can transiently induce hypoxia in tumors. We investigated the mechanism underlying the induction of transient hypoxia and the combination use of pyruvate to potentiate the anti-tumor effect of TH-302.), significantly delayed tumor growth. studies showed that pyruvate induces transient hypoxia by enhancing mitochondrial oxygen consumption in tumor cells. TH-302 therapy can be potentiated by pyruvate pretreatment if started at the appropriate tumor size and oxygen concentration
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