Abstract 316: FTY720 enhances the efficacy of paclitaxel and of carboplatin in drug-resistant ovarian cancer cells
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Abstract Objectives: Our long-term goal is to develop effective therapies for ovarian cancer by targeting molecules that contribute to drug resistance in this tumor type. Preliminary RNA-seq data were generated using a patient-derived xenograft model. These data identified the sphingosine-1-phosphate (S1P) signaling pathway as one of the pathways most affected by carboplatin and paclitaxel, the current standards of care for ovarian cancer. We then examined whether a synthetic analog of sphingosine, FTY720, enhanced the cytotoxicity of platinum and taxane resistant ovarian cancer cell lines. Methods: To assess the efficacy of FTY720 + carboplatin and of FTY720 + paclitaxel, we exposed three pairs of parental and drug resistant human ovarian cancer cell lines to each combination. The cell lines used were: SKOV3-ip1 and SKOV3-TR (taxane resistant), A2780 and A2780-CP20 (platinum resistant), and HeyA8 and HeyA8-MDR (taxane-platinum resistant). We used alamarBlue cell proliferation assays to determine the efficacy of FTY720 as a single agent or in combination with paclitaxel or carboplatin, and immunoblots to assess the expression of proteins involved in the S1P pathway. Results: FTY720 as a single agent decreased cell viability in a dose-dependent manner in all three pairs of cell lines, with IC50 values ranging from 5 to 8 μM. When cells were exposed to the IC50 of FTY720 + a range of concentrations of carboplatin or paclitaxel, FTY720 had little effect in any of the three parental cell lines and in SKOV3-TR cells. Interestingly, however, FTY720 decreased the IC50 of carboplatin 15- to 16-fold and the IC50 of paclitaxel 20- to 90- fold in A2780-CP20 and HeyA8-MDR cells, respectively. We also observed that FTY720 altered the expression of sphingosine kinase2, S1P lyase, and acid ceramidase, each of which contributes to the ceramide-sphingosine-S1P rheostat that tightly regulates expression of S1P pathway proteins. Conclusions: Our data show that FTY720 sensitized drug resistant ovarian cancer cell lines A2780-CP20 and HeyA8-MDR to carboplatin and to paclitaxel 15- to 90-fold. The data suggest that the S1P pathway may contribute to carboplatin and paclitaxel resistance in this cell type. We propose that proteins of the S1P pathway merit further study as effective molecular targets in drug resistant ovarian cancer cells. Citation Format: Kelly M. Kreitzburg, Ronald D. Alvarez, Charles N. Landen, Karina J. Yoon. FTY720 enhances the efficacy of paclitaxel and of carboplatin in drug-resistant ovarian cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 316.Keywords:
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Abstract The treatment of childhood cancer with chemotherapy drugs can result in infertility in adulthood. Newer generations of drugs are developed to replace parent drugs, with the potential benefits of less toxic side effects. For platinum alkylating-like drugs, in contrast to the parent compound cisplatin, the newer-generation drug carboplatin is reported to have reduced toxicity in some respects, despite being administered at 5–15 times higher than the cisplatin dose. Whether carboplatin is also less toxic than cisplatin to the reproductive system is unknown. Here we compare the gonadotoxic impact of cisplatin and carboplatin on female and male mouse prepubertal gonads. In vitro cultured CD1 mouse ovaries or testis fragments were exposed to either cisplatin or carboplatin for 24 h on Day 2 of culture and analysed by Day 6. A dose response for each drug was determined for the ovary (0.5, 1 & 5 μg/ml cisplatin and 1, 5 & 10 μg/ml carboplatin) and the testis (0.01, 0.05 & 0.1 μg/ml cisplatin and 0.1, 0.5 & 1 μg/ml carboplatin). For the ovary, unhealthy follicles were evident from 1 μg/ml cisplatin (73% unhealthy, P = 0.001) and 5 μg/ml carboplatin (84% unhealthy, P = 0.001), with a concomitant reduction in follicle number (P = 0.001). For the testis, the proliferating germ cell population was significantly reduced from 0.05 μg/ml cisplatin (73% reduction, P = 0.001) and 0.5 μg/ml carboplatin (75% reduction, P = 0.001), with no significant impact on the Sertoli cell population. Overall, results from this in vitro animal model study indicate that, at patient equivalent concentrations, carboplatin is no less gonadotoxic than cisplatin.
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The recurrence and prognosis of advanced cervical cancer patients is an unresolved medical need. To improve prognosis and bring new strategies to more curable stages of the disease, such as high-risk locally advanced disease patients and low metastatic or small volume disease patients. After culturing cervical cancer cells in vitro , they were treated with different concentrations of cisplatin and carboplatin drugs for 24, 48, and 72 hours respectively. Detected the inhibitory rate of different treatment groups on cervical cancer cells using CCK-8 detection, To observe live and dead cells through staining experiments. The results showed that different concentrations of cisplatin and carboplatin have significant inhibitory effects on cervical cancer cells. However, the inhibitory effect of cisplatin and carboplatin in the high concentration group on cervical cancer cells were significantly greater than that in the low concentration treatment group. The sensitivity of cervical cancer cells to cisplatin was similar with carboplatin, and the sensitivity to cisplatin was better than that of carboplatin. We believe that targeted therapy can be combined with chemotherapy drugs to enhance the anti-tumor effect of cisplatin. When the toxic side effects of cisplatin cannot be overcome, carboplatin can be considered to replace cisplatin in the treatment of cancer.
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Objective:To evaluate the effect of cisplatin and carboplatin using chemosensitivity testing,and compare their cell toxicity and provide experimental evidence for clinical application.Methods:1.The mensuration of ATP standard curve.2.An ATP-CVA test was used to determine the drug sensitivity of Hela cells、Caski cells、Siha cells.The drug were cisplatin and carboplatin and the concentration were 0.5×PPC,1×PPC and 2×PPC respectively.Results:1.In a range of 10~(-9)-10~(-5) mol/ml,there is a linear relationship between the log ATP and the log luminescence(Y=0.892X+10.257,correlation coefficient r=0.998)(P0.001).2.At the concentration of 0.5×PPC、1×PPC and 2×PPC,the restraint rate of cisplatin of Hela cells were 53.5%、69.2% and 100% respectively,the restraint rate of carboplatin of Hela cells were 56.1%、64.2% and 98% respectively;the restraint rate of cisplatin of Siha cells were 78.3%、84% and 95% repectively,the restraint rate of carboplatin of Siha cells were 69.5%、77.8% and 98% respectively;the restraint rate of cisplatin of Caski cells were 36%、45% and 52.6%,respectively,the restraint rate of carboplatin of Caski cells were 40%、41.7% and 42.3%,respectively;the differences were not significant(P0.05).Conclusion:The difference of cell toxicity between cisplatin and carboplatin was not significant,and carboplatin is better than cisplatin in the chemotherapy of cervical cancer for its little side effect.
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Objective:To provide experimental proofs for cisplatin combined with carboplatin in therapy of osteosarcoma through comparing the cytotoxity of half dose cisplatin combined with half dose carboplatin,cisplatin and arboplatin in osteosarcoma cell line(OS-732).Methods:OS-732 cells were treated by IC 50 of cisplatin,IC 50 of carboplatin,or 1/2 IC 50 cisplatin combined with 1/2 IC 50 carboplatin,and cultured 48h or 72h.Then their viability was determined by the colorimetric MTT assay.Results:When cells were cultured for 48hrs,cytotoxicities of group IC 50 cisplatin,IC 50 carboplatin and 1/2 IC 50 cisplatin+1/2 IC 50 carboplatin for OS-732 cells had no significant difference( P 0 05);when cells were cultured for 72 hrs,cytotoxicities of group IC 50 carboplatin and group 1/2 IC 50 cisplatin+1/2 IC 50 carboplatin for OS-732 cells were higher than that of group IC 50 cisplatin( P 0 05)Conclusion:Cisplatin combined with carboplatin as a “single agent” appears to be as active as cisplatin or carboplatin alone in
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Abstract Cisplatin and carboplatin are integral parts of many antineoplastic management regimens. Both platinum analogues are potent DNA alkylating agents that robustly induce genomic instability and promote apoptosis in tumor cells. Although the mechanism of action of both drugs is similar, cisplatin appears to be more cytotoxic. In this study, the genotoxic potential of cisplatin and carboplatin was compared using chromosomal aberrations (CAs) and sister-chromatid exchange (SCE) assays in cultured human lymphocytes. Results showed that cisplatin and carboplatin induced a significant increase in CAs and SCEs compared to the control group ( p <0.01). Levels of induced CAs were similar in both drugs; however, the magnitude of SCEs induced by cisplatin was significantly higher than that induced by carboplatin ( p <0.01). With respect to the mitotic and proliferative indices, both cisplatin and carboplatin significantly decreased mitotic index ( p <0.01) without affecting the proliferative index ( p >0.05). In conclusion, cisplatin was found to be more genotoxic than carboplatin in the SCE assay in cultured human lymphocytes, and that might explain the higher cytotoxicity of cisplatin.
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Objective To observe the cytotoxicity of cisplatin combined with carboplatin on osteosarcoma cell line OS-732.Methods Using MTT assay,we obtained the mean IC50 of cisplatin and carboplatin for OS-732 cells.The OS-732 cells were incubated with following drugs for 48 or 72h: IC50 of cisplatin,IC50 of carboplatin,and 1/2 IC50 of cisplatin combined with 1/2 IC50 carboplatin.The cytotoxicity of each group was measured with MTT methods.Results The mean IC50 of cisplatin and carboplatin for osteosarcoma OS-732 cells for 48h was 7.6μg/ml and 199.0μg/ml respectively.The mean cytotoxicity index(CI) of 8.0μg/ml cisplatin, 200.0μg/ml carboplatin and 4.0μg/ml cisplatin+100.0μg/ml carboplatin for 48h were (54.7±5.3)%,(56.9±6.3)% and(57.5±5.7)% respectively(P0.05);and those for 72h were (65.7±4.5)%,(69.4±2.2)% and(68.4±3.6)% respectively,the cytotoxicity index increased significantly in groups containing carboplatin.Conclusion The combination of half dose cisplatin with carboplatin appears to be as active as cisplatin or carboplatin alone in full doses in treatment of osteosarcoma OS-732 cells in vitro.
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AbstractThe combination of carboplatin and paclitaxel is widely used to treat multiple solid tumors including ovarian, lung and breast cancer. Usually these drugs are given simultaneously with little regard to the importance of scheduling to obtain a maximal response. To investigate the importance of sequencing, the human breast Bcap37 and ovarian OV2008 cancer cell lines were exposed to carboplatin and paclitaxel in three different sequences: 1) pretreatment with paclitaxel followed by carboplatin; 2) pretreatment of carboplatin followed by paclitaxel and 3) simultaneous treatment with these two agents. The combination of carboplatin and paclitaxel resulted in antagonistic interactions when tumor cells were exposed to carboplatin prior to paclitaxel or exposed to the two drugs simultaneously, but there was little antagonistic interaction observed when paclitaxel was administered before carboplatin. Biochemical examination revealed that pretreatment or cotreatment of carboplatin inhibited paclitaxel-induced IκBα degradation and bcl-2 phosphorylation. Further analyses demonstrated that carboplatin could significantly interfere with the cytotoxic effects of paclitaxel on both mitotic arrest and apoptotic cell death unless paclitaxel was administered before carboplatin. These results indicate that the interaction between paclitaxel and carboplatin is highly schedule dependent. The optimal schedule for this combination is sequential exposure of paclitaxel followed by carboplatin.
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