Upregulation of miRNA-200 family members in human paclitaxel resistant OVCAR-3/TP cells alters the sensitivity to carboplatin, but not paclitaxel
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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.
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Objective:To investigate the inhibitory effects of paclitaxel alone or combined with cisplatin against human breast cancer line MCF-7 in vitro,and to explore the related mechanisms with MAPK pathway and Bcl-2 gene family.Methods: MCF-7 cells were treated by paclitaxel with or without cisplatin,and the proliferation and 50% inhibitory concentration(IC50) were calculated by cell counting kit-8 assay.The effects of ERK pathway inhibitor(U0126) and JNK pathway inhibitor(sp600125) on cell proliferation were also observed.Flow cytometry was used to determine cell cycle distribution,and Western blot was used to detect the protein expression level changes of MAPK pathway members,Bcl-2 and Bax when cells were given different treatments.Results: Paclitaxel(0.025～0.400 μmol/L) combined with cisplatin(1～16 μmol/L) showed an obvious synergistic effect(CI 0.95).Sp600125 could significantly inhibit MCF-7 growth in vitro.Sp600125 combined with paclitaxel or cisplatin had a better antitumor activity than paclitaxel or cisplatin used alone.When treated with paclitaxel and cisplatin together,the cells at G2/M phase were less than paclitaxel group but more than cisplatin group.Combination of paclitaxel and cisplatin was found to decrease p-ERK,Bcl-2 protein levels in contrast with paclitaxel group or cisplatin group and increase p-JNK/p-SAPK,p-p38 protein levels in contrast with control group after 48 hours.Conclusion: Combination of paclitaxel and cisplatin in vitro showed synergistic effect.JNK pathway inhibitor combined with paclitaxel and cisplatin showed more powerful inhibition on MCF-7 cells than the two drug combination.Combination of paclitaxel and cisplatin seems to limit the accumulation of MCF-7 cells in G2/M and activate JNK and p38 signal pathway while inhibit the activation of ERK signal pathway.
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Strategies to prevent the emergence of drug resistance will increase the effectiveness of chemotherapy treatment and prolong survival of women with ovarian cancer. The aim of our study is to determine the effects of NSC23925 on preventing the development of paclitaxel resistance in ovarian cancer both in cultured cells in vitro and in mouse xenograft models in vivo, and to further elucidate these underlying mechanisms. We first developed a paclitaxel-resistant ovarian cancer cell line, and demonstrated that NSC23925 could prevent the introduction of paclitaxel resistance by specifically inhibiting the overexpression of P-glycoprotein (Pgp) in vitro. The paclitaxel-resistant ovarian cancer cells were then established in a mouse model by continuous paclitaxel treatment in combination with or without NSC23925 administration in the mice. The majority of mice continuously treated with paclitaxel alone eventually developed paclitaxel resistance with overexpression of Pgp and antiapoptotic proteins, whereas mice remained sensitivity to paclitaxel and displayed lower expression levels of Pgp and antiapoptotic proteins after administered continuously with combination of paclitaxel-NSC23925. Paclitaxel-NSC23925-treated mice experienced significantly longer overall survival time than paclitaxel-treated mice. Furthermore, the combination of paclitaxel and NSC23925 therapy did not induce obvious toxicity as measured by mice body weight changes, blood cell counts and histology of internal organs. Collectively, our observations provide evidence that NSC23925 in combination with paclitaxel may prevent the onset of Pgp or antiapoptotic-mediated paclitaxel resistance, and improve the long-term clinical outcome in patients with ovarian cancer.
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The present study deals with the evaluation of the efficacy of oxaliplatin and paclitaxel combination as a potential strategy in controlling HNSCC cell proliferation and the assessment of correlation between occurrence of apoptosis and changes in expression of survivin (IAP). The panel cell lines included two HNSCC cell lines (Cal27 and NT8e) and one normal cell line (293) with differential level of survivin expression in accordance with chemosensitivity. The cytotoxicity and effect of drugs on apoptosis was determined, separately and in combination. Combined treatment of cells with paclitaxel and oxaliplatin resulted in significantly higher cytotoxicity as compared to individual single drug treatment. Cytotoxicity was prominent in paclitaxel to oxaliplatin (pacl-oxal) sequence treatment with an approximate two-fold increase in apoptosis as compared to oxaliplatin to paclitaxel (oxal-pacl) sequence treatment. Paclitaxel treatment also caused increased survivin expression showing reduced apoptosis at low concentration. Oxaliplatin, when combined with paclitaxel, decreased the survivin level with increased cell death. Inhibition of survivin by a small interfering RNA (siRNA) method also increased the sensitivity of the cancer cell lines to paclitaxel whereas over-expression of survivin in the transfected 293-cell line provided resistance. In conclusion, the interaction between drugs was synergistic and schedule-dependent. Survivin played a critical role in paclitaxel resistance through the suppression of apoptosis, and a significant induction of apoptosis was observed when oxaliplatin was combined with paclitaxel at least in part by the down-regulation of survivin. Keywords: Survivin, oxaliplatin, paclitaxel, chemotherapy, HNSCC, apoptosis.
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Previous researches confirmed that the mammalian target of rapamycin (mTOR) plays an important role in the tumorigenesis and development of malignant tumors. This study was to investigate the effect of rapamycin, a selective inhibitor of mTOR, combined paclitaxel on the apoptosis of ovarian cancer cell lines A2780 and SKOV3, and explore the molecular mechanism.A2780 and SKOV3 cells were treated with rapamycin and (or) paclitaxel. Cell proliferation was assessed by MTT assay. The interaction of rapamycin and paclitaxel was estimated by Jin Zhengjun's method. Cell apoptosis was detected by flow cytometry (FCM). The expression of survivin in A2780 and SKOV3 cells was detected by reverse transcription-polymerase chain reaction (RT-PCR).When treated with rapamycin combined paclitaxel for 72 h, the proliferation inhibition rate was 34.9% for A2780 cells and 37.1% for SKOV3 cells, which was significantly higher than those of the cells treated with rapamycin or paclitaxel alone (P<0.01). These 2 drugs showed synergistic effect (q>1.15). The apoptosis of A2780 and SKOV3 cells were induced by rapamycin and paclitaxel; the apoptosis rate reached to the peak when the cells were treated with rapamycin combined paclitaxel. The expression of survivin in A2780 and SKOV3 cells was declined obviously after treatment of rapamycin combined paclitaxel.Rapamycin and paclitaxel could inhibit proliferation and induce apoptosis of A2780 and SKOV3 cells in vitro, and down-regulate the expression of survivin. These 2 drugs have synergistic effect on cell proliferation.
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Salt-induced kinase 2 (SIK2) is a serine-threonine kinase that regulates centrosome splitting, activation of PI3 kinase and phosphorylation of class IIa HDACs, affecting gene expression. Previously, we found that inhibition of SIK2 enhanced sensitivity of ovarian cancer cells to paclitaxel. Carboplatin and paclitaxel constitute first-line therapy for most patients with ovarian carcinoma, producing a 70% clinical response rate, but curing <20% of patients with advanced disease. We have asked whether inhibition of SIK2 with ARN-3261 enhances sensitivity to carboplatin in ovarian cancer cell lines and xenograft models. ARN-3261-induced DNA damage and apoptosis were measured with γ-H2AX accumulation, comet assays, and annexin V. ARN-3261 inhibited growth of eight ovarian cancer cell lines at an IC50 of 0.8 to 3.5 µM. ARN-3261 significantly enhanced sensitivity to carboplatin in seven of eight ovarian cancer cell lines and a carboplatin-resistant cell line tested. Furthermore, ARN-3261 in combination with carboplatin produced greater inhibition of tumor growth than carboplatin alone in SKOv3 and OVCAR8 ovarian cancer xenograft models. ARN-3261 enhanced DNA damage and apoptosis by downregulating expression of survivin. Thus, a SIK2 kinase inhibitor enhanced carboplatin-induced therapy in preclinical models of ovarian cancer and deserves further evaluation in clinical trials.
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