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Cross-resistance of cisplatin selected cells to anti-microtubule agents: Role of general survival mechanisms.

Translational oncology (2020-11-01)
Ruchi P Patel, Skyler Kuhn, Da Yin, Jordan M Hotz, Frances A Maher, Robert W Robey, Michael M Gottesman, Sachi Horibata
ABSTRACT

Although the first line of therapy for epithelial ovarian cancer typically consists of taxane-platinum combination therapy, many patients develop a platinum-resistant tumor within a year. Several previous studies have looked at this cross-resistance between cisplatin and anti-microtubule drugs, but their findings have been somewhat conflicting. Here, we developed cisplatin-resistant cell lines that are resistant to low and high levels of cisplatin and explored the effects of three anti-microtubule drugs (paclitaxel, vincristine, and colchicine) on the parental and cisplatin-resistant cells. We found that cells resistant to lower levels of cisplatin were no more resistant to anti-microtubule drugs than parental cells, while cells that were resistant to higher levels of cisplatin had a subpopulation of cells that were cross-resistant to anti-microtubule drugs, clarifying discrepancies within the field. We then isolated this subpopulation by applying selective pressure with anti-microtubule drugs and performed RNA sequencing and gene set enrichment analysis to identify resistance mechanisms. This subpopulation was found to express increased levels of pro-survival TNF/NFκB signaling, among other enriched pathways, suggesting that cross-resistance was due to more general survival mechanisms found in the cisplatin-selected cells.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Rhodamine 123, BioReagent, for fluorescence, ≥85% (HPLC)
Sigma-Aldrich
Colchicine, ≥95% (HPLC), powder
Sigma-Aldrich
Triton X-100, laboratory grade
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Paclitaxel, from Taxus brevifolia, ≥95% (HPLC), powder
Sigma-Aldrich
cis-Diammineplatinum(II) dichloride, crystalline
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Vincristine sulfate salt, 95.0-105.0% (HPLC), powder or crystals
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6-Phosphonohexanoic acid, 97%
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Propidium iodide, ≥94.0% (HPLC)
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Fumitremorgin C, from Neosartorya fischeri, film
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Anti-phospho-RELA (pSer529) antibody produced in rabbit, affinity isolated antibody