Pharmacometabolomics of docetaxel-treated human MCF7 breast cancer cells provides evidence of varying cellular responses at high and low doses

Abstract

There is growing evidence that docetaxel, a microtubule-targeting agent like the other taxane paclitaxel, induces dual cytotoxicity mechanism according to dose level. Postgenomics screening technologies are now more and more applied to the elucidation of drug response mechanisms. Proton nuclear magnetic resonance spectroscopy-based pharmacometabolomics was here applied to get further insight into the response of human MCF7 breast carcinoma cells to docetaxel at high (clinical, 5 lM) and low (1 nM) doses. The global response to both doses was evaluated by nuclear morphology and DNA content, the latter as an index of cell proliferation and DNA ploidy. High dose provoked long-lasting cell cycle arrest in mitosis during the first 48 h of exposure to treatment and severe decrease in DNA content followed by significant amount of cell death. In contrast, at low dose, no long-lasting cell cycle arrest was observed on micrographies, and DNA content was decreased but less than at high dose (P \ 0.05), without significant cell death. This response was compared to biochemical alteration assessed by pharmacometabolomics. Thirty metabolites were identified and quantified. Metabolite profiling at clinical dose revealed time-dependent disorders in derivatives of glycolysis, lipid metabolism and glutathione metabolism.Comparison between high and low doses was performed at 72 h and showed common traits including the accumulation of cytidinediphosphocholine (95.0 and 96.9, respectively, P \ 0.03), the decrease in phosphatidylcholine (90.3 and 90.2, respectively, P \ 0.03), and gluthathione (90.6 and 90.6, respectively, P \ 0.03). Despite that, significant dosedependent differences were found in 12 of 30 measured metabolites. Among them, the most discriminant metabolites were polyunsaturated fatty acids (ratio of high-to-low dose of 14.8, P \ 0.05), glutamate, myoinositol, and homocysteine (ratio \ 0.4, P \ 0.05). In addition, the mechanism for glutathione decrease was different. At high dose, it resulted from extensive consumption with precursor starvation (glutamate: -89%, P \ 0.05) and increased glutathione S-transferase activity (95, P \ 0.01), whereas at low dose, it resulted from glutathione biosynthesis blockade with homocysteine accumulation (?144%, P \ 0.03) and decreased glutathione S-transferase activity (-70%, P \ 0.01). Altogether, this pharmacometabolomics analysis provides further evidence of the varying cellular responses at high and low doses of docetaxel in MCF7 breast cancer cells. The authors Mathilde Bayet-Robert and Daniel Morvan equally contributed to this work.

CCL2 influences the sensitivity of lung cancer A549 cells to docetaxel

“…DTX is widely used as a cancer treatment (6)(7)(8)(9)(10)(11)(12)(13)(14). However, the emergence of chemotherapeutic resistance iTHs universal and DTX-resistance responses have been observed in a number of patients (15).…”

“…Docetaxel (DTX) is a well-established anti-mitotic chemotherapy agent that functions by interfering with cell division (5). It is used to treat a number of cancer types including metastatic or advanced breast, prostate, thyroid, gastric, ovarian and lung cancer based on its pro-apoptosis potential and its inhibitory effect on angiogenesis and cell viability (6)(7)(8)(9)(10)(11)(12)(13)(14). DTX has also been demonstrated to upregulate growth/differentiation factor 15 and results in chemoresistance in prostate cancer (15).…”

Progestin modulates the lipid profile and sensitivity of breast cancer cells to docetaxel

“…Because fatty acid composition was analyzed only in cells surviving docetaxel treatment, this suggests increasing the oleic acid content of the cancer membranes alters its composition and enhances cell survival, as others have also suggested (Baritaki et al, 2007). Docetaxel treatment also increases polyunsaturated fatty acids in MCF7 breast cancer cells (Bayet-Robert et al, 2009), suggesting membrane fluidity as a survival mechanism not unique to T47D cells. Examination of saturation content between phospholipids and lipid droplets also suggests reciprocal lipid content between membrane and storage lipid droplets.…”

Construction of multi-gene classifier for prediction of response to and prognosis after neoadjuvant chemotherapy for estrogen receptor positive breast cancers

“…It is well known that metabolic change occurs during carcinogenesis [22,23], and it is reported that the metabolic status of tumor cells is associated with proliferation and chemo-sensitivity [24][25][26]. MPCP155 includes some interesting metabolic genes such as ACADSB, SLC27A2 [27], PPARD, BLM, KPNA2 [28], FASN [29][30][31][32], IDH2 [33][34][35], ACSL1 [36], ME1 [37], which are also reported to be associated with carcinogenesis or cancer proliferation.…”