Abstract 5294: Inhibition of mitochondrial transport in neuronal cells by microtubule-targeting drugs eribulin, ixabepilone, paclitaxel, and vincristine

Abstract

Abstract Peripheral neuropathy can be a serious, dose-limiting side effect of cancer treatment with microtubule-targeting drugs. We hypothesize that inhibition of mitochondrial transport contributes to the neuropathic “dying back” of peripheral neurons often seen with chemotherapy-induced peripheral neuropathy. We examined the effects of eribulin (ERB), vincristine (VCR), paclitaxel (PAC), and ixabepilone (IXA) on mitochondrial trafficking in neurites of SK-N-SH human neuroblastoma cells. The concentration range used was chosen to reflect their relative potencies for inhibition of cancer cell proliferation (3× IC50: ERB, 2.4 nM, VCR, 8.4 nm, IXA, 23 nM, PAC, 33nM). In control cells, mitochondria moved anterogradely at a velocity of 14 µm/min, and retrogradely at 16 µm/min. At ∼ 3× IC50 antiproliferative values, ERB and VCR did not significantly inhibit anterograde trafficking velocity, whereas IXA and PAC reduced it by 30%. At sufficiently high concentrations, ERB (10 nM, 10× IC50) and VCR (10 nM, 4× IC50) reduced anterograde velocity to the same extent as PAC and IXA, by ∼30%. Retrograde trafficking was not significantly inhibited by any of the drugs. The drugs also reduced the number of moving mitochondria. In control cells, an average of 4.3 mitochondria moved per visualized cell area. The four drugs, over a range of the concentrations, reduced the number of moving mitochondria by 19-47%, with no apparent differences between drugs. FCCP (10 µM), a mitochondrial membrane depolarizing compound, also reduced the number of moving mitochondria by 39%, but, interestingly, did not inhibit the mitochondrial trafficking velocity. The more potent antiproliferative drugs ERB and VCR did not inhibit mitochondrial trafficking velocity at 3× IC50 concentrations, while the less potent antiproliferative drugs PAC and IXA inhibited anterograde trafficking velocity. This may be due in part to differences in drug-microtubule binding; ERB and VCR bind primarily to microtubule ends, while TAX and IXA bind along the lengths of the microtubules. Additionally, structural effects on microtubules, such as bundling, curved microtubules, and shortened microtubules, may influence the ability of kinesin to “walk” along the microtubule surface. All four drugs reduced the number of moving mitochondria, possibly as a result of mitochondrial depolarization, suggested by the effects of the mitochondrial depolarizing compound, FCCP. These results suggest that the antiproliferative potency of the drugs, as well as the binding location on microtubules and/or drug-induced changes in microtubule structure, contribute to the drugs' neurotoxic effects on mitochondrial trafficking velocity in the axons of peripheral neurons, while the increase in stalled mitochondria may be due to a mitochondrial depolarization effect of the drugs. This work was funded by Eisai Inc. Note: This abstract was not presented at the meeting. Citation Format: Jennifer A. Smith, Gregoriy Smiyun, Leslie Wilson, Stuart Feinstein, Mary Ann Jordan. Inhibition of mitochondrial transport in neuronal cells by microtubule-targeting drugs eribulin, ixabepilone, paclitaxel, and vincristine. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5294. doi:10.1158/1538-7445.AM2014-5294