Abstract P284: The Chemotherapeutic Agent Docetaxel Disrupts Mitochondrial Energetics in 3D Human Bioengineered Myobundles
Torres Alcalde, MJ; Zang, X; Slentz, DH; Koves, TR; Truskey, GA; Muoio, DM
Published in: Circulation
Taxanes (i.e. docetaxel, (TAX)) comprise the first line-treatment for breast cancer (BC), mostly in combination with anthracyclines like doxorubicin (DOX). The efficacy of these drugs as antineoplastic agents has helped to boost 10-year survival rates to > 90%, leading to a fast-growing population of over 3 million BC survivors in the US. However, epidemiological evidence shows that the highly abrasive nature of these therapies can give rise to a vicious cycle of metabolic decline and physical inactivity that compromises quality of life and increases risk of numerous musculoskeletal and cardio-metabolic disorders including arthritis, sarcopenic obesity, cardiovascular disease and type 2 diabetes. Major side effects of TAX include peripheral neuropathy, arthralgia, myalgia and muscle weakness. Taxanes act primarily by stabilizing microtubules (MTs), which causes cell cycle arrest. Importantly, MT dynamics can also impact mitochondrial function. For example, the MT protein unit, tubulin, can bind to the outer mitochondrial protein channel, VDAC, and thereby affect ATP transport to the cytosol. Herein, we sought to test the hypothesis that TAX exacerbates DOX-induced mitochondrial dysfunction, which is thought to underlie anthracyclines’ cardiotoxicity. To this end, we leveraged a newly developed 3-D bioengineered model of human muscle organoids (myobundles), derived from primary human skeletal muscle progenitor cells (HSkM), to study mechanisms of TAX-induced myotoxicity and its interactions with DOX. Preliminary findings in primary HSkM cells exposed to 3 daily x 3 h treatments with TAX (1 - 100 nM) +/- 10 nM DOX caused a robust ~10-fold acetylation of a-tubulin at lysine 40 (AcK40), reflecting marked stabilization of MTs. TAX treatment decreased basal and ATP-linked respiration (JO
) up to 30 % (p<0.05), in a dose-dependent manner. However, maximal uncoupled JO
(+FCCP) remained unchanged, suggesting TAX disrupts mitochondrial thermodynamics and energy transfer, rather than maximal oxidative phosphorylation capacity. Exposure of 3D myobundles to a TAX+/-DOX regimen that mimicked human pharmacokinetics post-infusion led to a 30-fold increase (p<0.005) in AcK40 a-tubulin. TAX alone induced a biphasic JO
response to ADP (KM
2- and 4-fold higher, p<0.05), but when combined with DOX there was a 50 % loss in maximal JO
(p<0.005) with no changes in KM
. We hypothesize that the TAX-driven stabilization of MTs leads to detrimental MT-mitochondria interactions that disrupt ATP/ADP transfer between cellular compartments, exacerbating DOX toxicity and ultimately impairing muscle function. The present findings provide novel insights into the mechanisms of TAX-induced myotoxicities, which is of paramount importance for developing therapeutic strategies to improve cardiovascular health and quality of life of long-term breast cancer survivors.
