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The biguanides, anti-diabetic drugs for type 2 diabetes, have been identified to reduce carcinogenesis and effectively disrupt cancer cell proliferation by inhibiting complex I 5. Recent studies have demonstrated OXPHOS inhibitors as anticancer therapeutics targeting the mitochondrial complex I. Among OXPHOS proteins, complex I is highlighted as an attractive target for high OXPHOS tumors such as pancreatic ductal adenocarcinoma (PDAC), in which the refractory cancers are enriched in complex I at protein and mRNA levels 3, and invasive breast tumors, in which mitochondrial OXPHOS is favored to produce ATP via enhancement of PGC-1О± 4. Cancer cells also preferentially utilize mitochondrial OXPHOS for energy production in glucose-limiting conditions 2. The certain aggressive subtypes of cancer cells were identified to be highly dependent on oxidative phosphorylation (OXPHOS) 1.

Mitochondrial metabolism significantly contributes to cancer proliferation in various ways including ATP production, redox homeostasis, and other metabolic reprogramming. These results suggest that NMac1 and NMac24 have the potential as anti-cancer agents having cytotoxic effects selectively in glucose restricted cells. NMac1 and NMac24 effectively suppress cancer cell proliferation in 3D-spheroid in vivo-like models only under glucose starvation. Through the structureвЂ“activity relationship (SAR) study of NMac1 derivatives, NMac24 was identified as the most effective compound in anti-proliferation. These effects of NMac1 are provoked by a consequence of OXPHOS complex I inhibition. NMac1 causes significant activation of AMPK by decreasing ATP synthesis, lowers mitochondrial membrane potential (MMP, О”ОЁm), and inhibits oxygen consumption rate (OCR) under glucose starvation.

#Crystal report 10 registration key Activator

In this study, we found that a small molecule phenylbutenoid dimer NMac1 ( Nm23-H1 activator 1), (В±)-trans-3-(3,4-dimethoxyphenyl)-4-cyclohex-1-ene, a previously identified anti-metastatic agent, has novel anti-proliferative effect only under glucose starvation in metastatic breast cancer cells. Mitochondrial oxidative phosphorylation (OXPHOS) has become an attractive target in anti-cancer studies in recent years.