Codominance of cisplatin resistance in somatic cell hybrids

Abstract

Intrinsic or acquired resistance to cisplatin in cancer cells remains a major obstacle to successful chemotherapy. The clinically relevant genetic and molecular mechanisms of resistance have not yet been identified. Cisplatin-resistant (CP-r) human KB epidermoid carcinoma cell lines (HeLa) resistant to varying levels of cisplatin after single and multiple selection steps are cross-resistant to other platinum compounds and to methotrexate. Intraspecies hybrids of the sensitive and KB CP-r cells were fused with HeLa D98 OR CP-s, hypoxanthine-aminopterinthymidine (HAT) sensitive, ouabain resistant, to determine whether cisplatin resistance is dominant or recessive. Cell-cell hybridization between the sensitive cells and single-step or two-step KB CP-r cells both indicated codominance of cisplatin resistance compared to hybrids between sensitive cell lines (D98 OR xKB). The hybrids between sensitive cell lines (D98xKB) and a single-step CP-r KB cell line (D98xKB-CP.5) also were cross-resistant to carboplatin and methotrexate. In addition, the relatively slower growth rate of CP-r cells appears to be dominant. In the two-step CP-r KB cell line, KB-CP1, resistance is no more dominant than in the single-step CP-r KB cell line, KB-CP.5, suggesting that one of the two steps of resistance in KB-CP1 may not be dominant. These dominance data suggest that it might be possible to identify one or more genes responsible for cisplatin resistance by gene transfer from a resistant cell line to a sensitive cell line.

SIRT1 Contributes in Part to Cisplatin Resistance in Cancer Cells by Altering Mitochondrial Metabolism

“…Our previous research demonstrated that the cellular proliferation rate is reduced with increasing cisplatin resistance in CP-r cells (10). The utilization of glucose has been recognized as an important feature of tumor development.…”

“…Processes that require energy, such as fatty acid synthesis, protein synthesis, and cell growth are curtailed in CP-r cells (9, 10, 32), possibly through the effects of SIRT1 as a central modulator. Overexpressed SIRT1 in CP-r cells might result in a higher threshold for apoptosis by targeting numerous cellular factors.…”

“…Previous work in our lab revealed that the growth rate and uptake of different nutrients were significantly reduced in cisplatin-resistant (CP-r) cells with increasing cisplatin resistance (9, 10). SIRT1, a known nutrient metabolism regulator, was measured in CP-r cells in the current study.…”

A pleiotropic defect reducing drug accumulation in cisplatin-resistant cells

“…In addition, the relatively slower growth rate of CP-r cells appears to be dominant. In the two-step CP-r KB cell line, KB-CP1, resistance is no more dominant than in the single-step CP-r KB cell line, KB-CP.5, suggesting that one of the two steps of resistance in KB-CP1 may be less dominant or recessive [20]. These dominance data suggest that it might be possible to identify one or more genes responsible for cisplatin resistance by gene transfer from a resistant cell line to a sensitive cell line.…”

“…In an attempt to understand and eventually isolate the gene(s) involved in cisplatin resistance, intraspecies hybrids have been formed between CP-s and CP-r KB epidermal carcinoma cells to determine whether cisplatin resistance is a dominant or recessive genetic trait [20]. The parental control KB-3-1 CP-s cell line, the single-step CP-r cell line (KB-CP.5), and a two-step resistant cell line (KB-CP1), respectively, were fused with a cisplatin sensitive cell line (HeLa D98 OR ), which is resistant to ouabain but sensitive to hypoxanthine-aminopterin-thymidine (HAT).…”