Anticancer strategy targeting the energy metabolism of tumor cells surviving a low-nutrient acidic microenvironment (R1).

Maeda, Yuki; Kikuchi, Ryota; Kawagoe, Junichiro; Tsuji, Takao; Koyama, Nobuyuki; Yamaguchi, Kazuhiro; Nakamura, Hiroyuki; Aoshiba, Kazutetsu

OBJECTIVE Tumor cells experience hypoxia, acidosis, and hypoglycemia. Metabolic adaptation to a glucose shortage is essential to maintain tumor cell survival because of their high glucose requirement. This study aimed to study the hypothesis that acidosis might promote tumor survival during a glucose shortage and if so, to explore a novel drug targeting metabolic vulnerability to glucose shortage. METHODS Cell survival and bioenergetics metabolism were assessed in lung cancer cell lines. Our in-house small-molecule compounds were screened to identify those that kill cancer cells under low-glucose conditions. Cytotoxicity against non-cancerous cells was also assessed. Tumor growth was evaluated in vivo using a mouse engraft model. RESULTS Acidosis limited the cellular consumption of glucose and ATP, causing tumor cells to enter a metabolically dormant but energetically economic state, which promoted tumor cell survival during glucose deficiency. We identified ESI-09, a previously known exchange protein directly activated by cAMP (EAPC) inhibitor, as an anticancer compound that inhibited cancer cells under low-glucose conditions, even when associated with acidosis. Bioenergetic studies showed that independent of EPAC inhibition, ESI-09 was a safer mitochondrial uncoupler than a classical uncoupler and created a futile cycling of mitochondrial respiration leading to decreased ATP production, increased ATP dissipation, and fuel scavenging. Accordingly, ESI-09 exhibited more cytotoxic effects under low-glucose conditions than under normal glucose conditions. ESI-09 was also more effective than actively proliferating cells on quiescent glucose-restricted cells. Cisplatin showed opposite effects. ESI-09 inhibited tumor growth in lung-cancer engraft mice. CONCLUSIONS This study highlights the acidosis-induced promotion of tumor survival during glucose shortage and demonstrates that ESI-09 is a novel potent anticancer mitochondrial uncoupler that targets a metabolic vulnerability to glucose shortage even when associated with acidosis. The higher cytotoxicity under lower than normal glucose conditions suggests that ESI-09 is safer than conventional chemotherapy, can target the metabolic vulnerability of tumor cells to low-glucose stress, and is applicable to many cancer cell types.