Biguanides sensitize leukemia cells to ABT-737-induced apoptosis by inhibiting mitochondrial electron transport

Abstract

Metformin displays antileukemic effects partly due to activation of AMPK and subsequent inhibition of mTOR signaling. Nevertheless, Metformin also inhibits mitochondrial electron transport at complex I in an AMPK-independent manner, Here we report that Metformin and rotenone inhibit mitochondrial electron transport and increase triglyceride levels in leukemia cell lines, suggesting impairment of fatty acid oxidation (FAO). We also report that, like other FAO inhibitors, both agents and the related biguanide, Phenformin, increase sensitivity to apoptosis induction by the bcl-2 inhibitor ABT-737 supporting the notion that electron transport antagonizes activation of the intrinsic apoptosis pathway in leukemia cells. Both biguanides and rotenone induce superoxide generation in leukemia cells, indicating that oxidative damage may sensitize toABT-737 induced apoptosis. In addition, we demonstrate that Metformin sensitizes leukemia cells to the oligomerization of Bak, suggesting that the observed synergy with ABT-737 is mediated, at least in part, by enhanced outer mitochondrial membrane permeabilization. Notably, Phenformin was at least 10-fold more potent than Metformin in abrogating electron transport and increasing sensitivity to ABT-737, suggesting that this agent may be better suited for targeting hematological malignancies. Taken together, our results suggest that inhibition of mitochondrial metabolism by Metformin or Phenformin is associated with increased leukemia cell susceptibility to induction of intrinsic apoptosis, and provide a rationale for clinical studies exploring the efficacy of combining biguanides with the orally bioavailable derivative of ABT-737, Venetoclax.

Mitochondria in cancer metabolism, an organelle whose time has come?

“…This causes an increase in the AMP/ATP ratio leading to the activation of adenosine monophosphate activated protein kinase (AMPK) which promotes catabolism and inhibits anabolic pathways like fatty acid synthesis [38]. In pre-clinical studies it sensitized leukemia stem cells to apoptosis [39]. Metformin is currently being tested in several clinical trials.…”

“…Phenformin is not reliant on transporters for cell entry and has increased potency for the mitochondrial membrane compared to metformin [45]. It also has a 10-fold higher potency than metformin in sensitizing leukemia cells Bcl-2 inhibiton [39]. It is also being explored in clinical trials as the toxicity previously observed was in patients with diabetes where the risk benefit ratio is significantly different from those suffering with a fatal malignancy.…”

Metformin reduces gastric cancer risk in patients with type 2 diabetes mellitus

“…In contrast to other antidiabetic drugs (including sulfonylurea, insulin, thiazolidinediones and incretin-based therapies) that may show an increased risk of cancer [ 10 - 16 ], metformin was first noted to be associated with a reduced risk of cancer in an observational study in 2005 [ 17 ]. Metformin has been shown to inhibit the growth and proliferation of cancer cells including the breast [ 18 ], endometrium [ 19 ], ovary [ 20 ], lung [ 21 ], thyroid [ 22 ], liver [ 23 ], pancreas [ 24 ], esophagus [ 25 ], stomach [ 26 ], colon [ 25 ], prostate [ 27 ], bladder [ 28 ], glioblastoma [ 29 ], and leukemic cells [ 30 ]. In consistent with findings in animals which showed a beneficial effect of metformin on the inhibition of carcinogenesis in at least 17 target organs [ 31 ], epidemiological studies demonstrated a protective effect of metformin on a variety of cancer types including thyroid cancer [ 32 ], oral cancer [ 33 ], colon cancer [ 34 ], breast cancer [ 35 ], endometrial cancer [ 36 ], ovarian cancer [ 37 ], prostate cancer [ 38 ], bladder cancer [ 39 ], kidney cancer [ 40 ] and cervical cancer [ 41 ].…”

Chronic myeloid leukemia stem cells and molecular target therapies for overcoming resistance and disease persistence

“…Earlier studies showed that stem cells utilize glucose-independent metabolic pathway, such as fatty-acid oxidation (FAO; also known as β-oxidation) or specific dipeptide species [42,43]. Notably, FAO is essential for maintenance and chemoresistance of LSCs, and proposed to be as a potential target for CML therapy [44]. Our findings indicate that the perturbation of the Warburg effect by IM activates FAO as compensatory energy supplier; however, AIC-47 inhibits FAO [41].…”