Mitochondrial complex I inhibitor deguelin induces metabolic reprogramming and sensitizes vemurafenib‐resistant BRAF^V600E mutation bearing metastatic melanoma cells

Abstract

Treatment with vemurafenib, a potent and selective inhibitor of mitogen‐activated protein kinase signaling downstream of the BRAFV600E oncogene, elicits dramatic clinical responses in patients with metastatic melanoma. Unfortunately, the clinical utility of this drug is limited by a high incidence of drug resistance. Thus, there is an unmet need for alternative therapeutic strategies to treat vemurafenib‐resistant metastatic melanomas. We have conducted high‐throughput screening of two bioactive compound libraries (Siga and Spectrum libraries) against a metastatic melanoma cell line (A2058) and identified two structurally analogous compounds, deguelin and rotenone, from a cell viability assay. Vemurafenib‐resistant melanoma cell lines, A2058R and A375R (containing the BRAFV600E mutation), also showed reduced proliferation when treated with these two compounds. Deguelin, a mitochondrial complex I inhibitor, was noted to significantly inhibit oxygen consumption in cellular metabolism assays. Mechanistically, deguelin treatment rapidly activates AMPK signaling, which results in inhibition of mTORC1 signaling and differential phosphorylation of mTORC1's downstream effectors, 4E‐BP1 and p70S6 kinase. Deguelin also significantly inhibited ERK activation and Ki67 expression without altering Akt activation in the same timeframe in the vemurafenib‐resistant melanoma cells. These data posit that treatment with metabolic regulators, such as deguelin, can lead to energy starvation, thereby modulating the intracellular metabolic environment and reducing survival of drug‐resistant melanomas harboring BRAF V600E mutations.

Metabolic Plasticity of Melanoma Cells and Their Crosstalk With Tumor Microenvironment

“…The efficacy of mitochondrial complex I inhibitors in melanoma treatment was also supported by Carpenter et al who demonstrated that deguelin strongly suppresses the proliferation of vemurafenib-resistant melanoma cells by blocking the mitochondrial complex I. Of note, deguelin induces selectively toxicity only in cancer cells, without affecting the viability of normal human melanocytes in vitro ( Table 1) (224).…”

Mitochondria as a target in cancer treatment

“…Multiple small molecules have been developed to inhibit this pathway at several levels. Tigecycline 66 inhibits translation of mitochondria mRNA into OXPHOS subunits; Gamitrinib 67 inhibition OXPHOS assembly; Deguelin, 68 metformin 69 and IACS‐010759 70 inhibits complex I in the OXPHOS pathway, while Gboxin 7 inhibits complex V…”

Deguelin suppresses non-small cell lung cancer by inhibiting EGFR signaling and promoting GSK3β/FBW7-mediated Mcl-1 destabilization

“…Accumulating evidence reveals that the natural product deguelin exhibits profound anti-cancer potentials in multiple human cancer models, including lung cancer 14 , hepatocellular carcinoma 15 , colorectal cancer 16 , esophageal carcinoma 17 , metastatic melanoma 18 , and breast cancer 19 . The molecular mechanism studies showed that delay of cell cycle progression by inhibition of Aurora B kinase, regulation of metabolisms, such as suppression of glycolysis, down-regulation of angiogenesis and metastasis, and activation of intrinsic apoptosis were related to deguelin-mediated anti-tumor effect [20][21][22] .…”