Novel Stony Brook taxanes are efficacious in paclitaxel-resistant ovarian cancer models both in vitro and in vivo
Abstrakt
Introduction/Background*Resistance of cancer cells to taxanes is a serious problem preventing successful therapy. Efforts are ongoing to synthesize novel taxanes efficacious against the resistant phenotype. Stony Brook taxanes (SB-Ts) have proven to have potential, but require further preclinical testing and more detailed study of their mechanism of action. Here, we aimed to evaluate the efficacy of several promising SB-Ts in resistant ovarian cancer models in vitro, and in vivo. We also studied the role of 3 candidate genes ABCC3, CPS1, and TRIP6 in SB-Ts cell death-inducing molecular mechanisms.
Methodology The NCI/ADR-RES ovarian cancer cell line was incubated with either paclitaxel or one of the second generation (SB-T-1214 and SB-T-1216) or third generation (SB-T-121402, SB-T-121605 and SB-T-121606) taxanes. Cell survival was measured as IC50 after 72 hours. Cell cycle analysis was performed using flow cytometry. Uptake of SB-Ts into cells was measured by HPLC. Female athymic mice Nude Crl: NU(NCr)-Foxn1nu (N=50) were used as the model organism for ovarian cancer by subcutaneous application of NCI/ADR-RES cells. In vivo efficacy of taxanes was measured after intraperitoneal application twice per week. Gene expression in tumour tissue was measured by RT-qPCR.
Result(s)*Compared to paclitaxel, NCI/ADR-RES cells showed 30x lower resistance to SB-T-1214, SB-T-1216, and SB-T-121402 and 50x lower to the 3rd generation taxanes SB-T-121605 and SB-T-121606. Cell cycle analysis showed the "1216" family to be more cytostatic than cytotoxic compared to "1214". Uptake of SB-T-1216 and its derivatives into cells was 6-15.5x higher than for paclitaxel. Treatment of mice (groups of 5) with regimen combining paclitaxel and SB-T-121605/-06 significantly slowed tumour growth and even reduced tumour volume after several applications. Doses of SB-Ts higher than 3 mg/kg caused severe toxicity. Both SB-T-121605 and SB-T-121606, but not paclitaxel, led to significant decrease in CPS1 and ABCC3 expression in vitro and in case of CPS1 also in vivo.
Conclusion*Third generation taxanes SB-T-121605 and SB-T-121606 are highly effective in a paclitaxel-resistant ovarian carcinoma model both in vitro and in vivo and warrant further investigation. SB-T treatment led to deregulation of CPS1 and ABCC3 expression that seems to play a role in their efficacy.