Novel cancer drug candidates inducing mitochondrial dysfunction in glucose deprivation condition
Bo-Kyung Kim1*, Jae-Jin Lee1, Ji-Wan Suh1, Kong-Joo Lee1** 1Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, Korea 120-750 *catarina618@hanmail.net; **kjl@ewha.ac.kr
Most cancer cells predominantly generate their energy through a high-rate of glycolysis, while normal cells generate energy through mitochondrial oxidative phosphorylation. Because of those rapid consumption of glucose, cancer cells have lower glucose concentrations than normal cells, and try to utilize mitochondria properly. With this reason, mitochondria is an attractive target for cancer therapeutics. We screened natural chemical libraries and found a compound inhibiting the proliferation of several cancer cell lines only in glucose depleted condition. This compound turned out to induce specific morphology change in glucose deprivation condition. This morphology changes in response to this compound treatment was from ATP depletion which activates AMPK and inhibits mTOR and ERK. To investigate whether this compound affects the mitochondria function, we examined cellular oxygen consumption rate (OCR) and mitochondrial membrane potential using tetramethylrhodamine (TMRM) in response to chemical treatment. The results demonstrate that this compound induced the mitochondrial dysfunction only in glucose depleted condition, not in normal condition, and suppressed cell proliferation. We employed this compounds for combined therapy with paclitaxel of in vitro three-dimensional (3D) tumor cell invasion in MDA-MB231 breast cancer cell line. This compound lowered paclitaxel concentration to obtain the similar efficacy. We further identified more potent compounds and these results suggest that these novel compounds can be a promising cancer drug candidates for targeting mitochondria under the glucose depleted condition.
This work was supported by the Global Research Lab Program (No. 2012K1A1A2045441) and Brain Korea 21 Plus project of National Research Foundation
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