Dichloroacetic acid (DCA) synergizes with the SIRT2 inhibitor Sirtinol and AGK2 to enhance anti-tumor efficacy in non-small cell lung cancer

Abstract

Combination chemotherapy is a potentially promising approach to enhance anticancer activity, overcome drug resistance, and improve disease-free and overall survival. The current study investigates the antitumor activity of sodium dichloroacetic acid (DCA) in combination with SIRT2 inhibitor Sirtinol and AGK2. We found that combining DCA with Sirtinol produced a synergistic therapeutic benefit in A549 and H1299 NSCLC cells in vitro and in a mouse A549 xenograft model. Synergistic potentiation of oxidative phosphorylation (OXPHOS) was observed, including decreased glucose consumption, decreased lactate production, increased OCR and increased ROS generation, possibly via co-targeting pyruvate dehydrogenase alpha 1(PDHA1). Mechanically, AGK2 and Sirtinol were found to increase the lysine-acetylation and decrease the serine-phosphorylation of PDHA1, which enabled the two inhibitors to synergize with DCA to further activate PDHA1. Besides, a AMPKα-ROS feed-forward loop was notably activated after the combined treatments compared with mono-therapy. Our results indicate that the combination of DCA and SIRT2 inhibitor may provide a promising therapeutic strategy to effectively kill cancer cells.

Combined use of arginase and dichloroacetate exhibits anti-proliferative effects in triple negative breast cancer cells

“…where it sensitized cancer cells to the chemotherapeutic agents. [26][27][28] We have observed that HA and DCA combination exhibited antiproliferative effect in MDA-MB 231 xenograft study. Here, we selected the dose of HA based on the dose used in a previous combination study with 5-fluorouracil.…”

“…In drug combinations, additive effect of recombinant HA with cisplatin or fluorouracil has been observed in HepG2, Hep3B and PLC/PRF/5 cells in inhibiting cell proliferation, increasing apoptosis and causing cell cycle arrest . DCA has been used with number of chemotherapeutic agents in cancers where it sensitized cancer cells to the chemotherapeutic agents …”

MiR-107 confers chemoresistance to colorectal cancer by targeting calcium-binding protein 39

“…[34][35][36] When combined with etoposide and cisplatin, carboplatin, platinum and its metabolite JM118, DCA was found to have significantly increased the antitumour effects. [37][38][39] There are two main mechanisms accounting for DCA's anticancer effect: 1) reversal of the Warburg effect to inhibit cancer cell proliferation and activate caspase-mediated apoptosis and 2) the oxidative elimination of lactic acid by the co-buffer action of pyruvate and hydrogen ions in the mitochondrial matrix. 40 Taken together, we disclose that miR-107/CAB39/AMPK/mTOR signal pathway is partially involved in the effect of DCA on increasing chemosensitivity, thus providing a promising target for CRC treatment.…”

Ginsenoside Rh2 reverses cyclophosphamide-induced immune deficiency by regulating fatty acid metabolism

“…To overcome the drug resistance and serious side effects of chemotherapy, a combined treatment approach holds promise for achieving a synergistic anticancer benefit . Das et al …”

“…To overcome the drug resistance and serious side effects of chemotherapy, a combined treatment approach holds promise for achieving a synergistic anticancer benefit. 26 Das et al 27 showed pairing targeted therapeutics with subtherapeutic doses of broad acting "network brake" drugs extended therapeutic utility while reducing whole body toxicity. Since its first discovery, CY has been used as an anticancer drug for more than 40 years in clinical practice, and remains to be a main chemotherapy drug for multiple cancers.…”