Anti-Cancer Drugs Induce Cytotoxicity by Disrupting Mitochondrial Oxidative Phosphorylation Complex I Activity and Stability — ASN Events
  1. Schedule
  2. Session 7: Poster Session B - Including Happy Hour & Trade Display
  3. Anti-Cancer Drugs Induce Cytotoxicity by Disrupting Mitochondrial Oxidative Phosphorylation Complex I Activity and Stability

Anti-Cancer Drugs Induce Cytotoxicity by Disrupting Mitochondrial Oxidative Phosphorylation Complex I Activity and Stability (#207)

Sze Chern Lim 1 , Kirstyn T Carey 1 , Matthew McKenzie 1
  1. Monash Institute of Medical Research, Clayton, VIC, Australia

Isoflavone derivatives, such as phenoxodiol, are small molecule inhibitors that exhibit cytotoxic anti-tumour activity, highlighting their potential for treating various types of human cancers. Second generation derivatives of phenoxodiol, ME-143 and ME-344 (MEI Pharma, Inc, USA), have been shown to induce either caspase-dependent or independent cell death and the activation of mitochondrial signalling pathways. However, their specific mitochondrial targets and how they affect mitochondrial function are unknown.
Previous in-vitro studies showed mitochondrial membrane potential and ATP/ADP ratios were reduced following treatment with isoflavone derivatives, suggesting it may inhibit oxidative phosphorylation (OXPHOS)1,2. Treatment of human primary fibroblasts, HEK293T, 143B osteosarcoma or HeLa cells with ME-143 or ME-344 resulted in an acute inhibition of mitochondrial respiration by up to 53%. Furthermore, this inhibition was only evident when OXPHOS complex I-linked substrates were used (and not complex II-linked), suggesting those compounds directly inhibit OXPHOS complex I activity. This was confirmed in isolated mitochondria, with ME-143 and ME-344 both inhibiting complex I activity by 86 or 71% in a similar fashion to the classic complex I inhibitor rotenone.
In addition to this inhibition, Blue Native-PAGE and western blot analysis revealed that steady-state levels of mature OXPHOS complexes I and IV were reduced following 4 hours of ME-143 or ME-344 treatment. Similarly, steady-state levels of the individual protein subunits of these complexes were reduced, suggesting the compounds induce OXPHOS complex degradation.
Our findings propose that the anti-tumour activities of ME-143 and ME-344 are due to direct inhibition of OXPHOS complex I activity. This inhibition results in a reduction of mitochondrial respiration and the loss of mitochondrial membrane potential, leading to the destabilization of OXPHOS complexes. These mitochondrial defects ultimately lead to the permeabilization of the mitochondrial membrane and the induction of cell death. Our work highlights the potential of ME-143 and ME-344 for cancer treatment.

  1. 1. Alvero, A.B., Montagna, M.K., Chen, R., Kim, K.H., Kyungjin, K., Visintin, I., Fu, H.-H., Brown, D., and Mor, G. (2009). NV-128, a novel isoflavone derivative, induces caspase-independent cell death through the Akt/mammalian target of rapamycin pathway. Cancer 115, 3204-3216.
  2. 1. Alvero, A.B., Montagna, M.K., Chen, R., Kim, K.H., Kyungjin, K., Visintin, I., Fu, H.-H., Brown, D., and Mor, G. (2009). NV-128, a novel isoflavone derivative, induces caspase-independent cell death through the Akt/mammalian target of rapamycin pathway. Cancer 115, 3204-3216. 2. Alvero, A.B., Montagna, M.K., Holmberg, J.C., Craveiro, V., Brown, D., and Mor, G. (2011). Targeting the Mitochondria Activates Two Independent Cell Death Pathways in Ovarian Cancer Stem Cells. Molecular Cancer Therapeutics 10, 1385-1393.