Effects of Hyperthermia Combined Platinum-based Drugs on Ovarian Cancer Cell Lines SKOV3
Abstract
To investigate the effects and mechanisms of hyperthermia combined with various platinum-based drugs cis-platinum (DDP), carboplatin (CBP), oxaliplatin (OXA) on the proliferation and apoptosis of ovarian cancer cell lines SKOV3. Methods SKOV3 cells were treated with different concentrations of anticancer drugs DDP (final concentration respectively 0, 1.25, 2.5, 5.0, 10.0, 20.0 μg/mL), CBP and OXA (both final concentration respectively 0, 2.5, 5.0, 10.0, 20.0, 40 μg/mL) at a temperature of 42 ℃ for hyperthermia or 37 ℃ for normal temperature. Methyl thiazolyl tetrazolium (MTT) method was used to test growth ratios of ovarian cancer cell lines SKOV3. Real-time PCR was adopted to detect the expression level of excision repair cross-complementing group 1 (ERCC1) and Survivin mRNA in SKOV3 cells. Results DDP, CBP and OXA inhibited the growth of SKOV3 in a dose-dependent manner （P<0.05). Hyperthermia could increase the sensitivity of SKOV3 to cis-platinum，carboplatin and oxaliplatin （P<0.05). The half inhibitory concentration (IC50） values of DDP, CBP and OXA were （7.271±0.096） μg/mL, （37.609±0.779） μg/mL and （28.328±0.698） μg/mL respectively. When combined with hyperthermia, the IC50 values of DDP, CBP, and OXA were （2.075±0.244） μg/mL, （19.591±0.453） μg/mL, （19.089±0.424） μg/mL （P<0.05). The increased sensitivity index was 2.075±0.244 for cis-platinum, 1.92±0.044 for carboplatin, 1.484±0.039 for oxaliplatin. After the treatment of hyperthermia, the expression of ERCC1 and Survivin mRNA showed downward trend. ERCC1 decreased more significantly in the group of hyperthermia combined with carboplatin, and Survivin decreased more significantly in the group of hyperthermia combined with oxaliplatin (P<0.05). Conclusion Hyperthermia can enhance the sensitivity of ovarian cancer SKOV3 cells to platinum-based drugs, which may be related to the down regulation of ERCC1 and Survivin expression.
Keywords: Ovarian cancer, SKOV3, Hyperthermia, ERCC1, Survivin
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Tentes ААК, Korakianitis OS. Kakolyris S. et al. Cytoreductive surgery and perioperative intraperitoneal chemotherapy in recurrent ovarian cancer. Tumori, 2010; 96 (3):411-416.
Jemal A, Siegel R. Xu J. et al. Cancer statistics, 2010. CA- Cancer J Clin,2010;60(5) ;277-300.
Siegel R. Naishadham D, Jemal A. Cancer statistics. 2013. CA- Cancer J Clin,2013;63( 1): 11-30.
Fukao H, Ikeda M. Ichikawa T, et al. Effect of hyperthermia on the viability and fibrinolytic potential of human cancer cell lines. Clin Chim Acta,2002;296( 1-2): 17-20.
Sawaji Y, Sato Y, Seiki M. et al. Heat shock-mediated transient increase in intracellular ЗЧ6 сусНс AMP results in tumor specific suppression of membrane type 1-matricx metalloproteinase production and progclatinase Aactivation. Clin Exp Metastasis,2000; 18(2); 131-146.
Xu XM« Yuan GJ, Li QW, et al. Hyperthermia inhibits transforming growth factor beta-induced epithelial- mesenchymal transition ( EMT ) in HepG2 hepatocellular carcinoma cells. Hepato-gastroenterol, 2012; 59 ( 119 ): 2059- 2063.
Guo Y, Ma J, Wu L, et al. Hyperthermia-induced NDRG2 upregulation inhibits the invasion of human hepatocellular carcinoma via suppressing ERK1/2 signaling pathway. PloS One»2013;8(4):e61079.
Argenta PA, Sueblinvong T, Geller MA, et al. Hyperthermic intraperitoneal chemotherapy with carboplatin for optimally- cytoreduced, recurrent, platinum-sensitive ovarian carcinoma; a pilot study. Gynecol Oncol,2013? 129(1):81-85.
Atmaca A, Al-Batran SE, Neumann A, et al. Whole-body hyperthermia ( WBH ) in combination with carboplatin in patients with recurrent ovarian cancer a phase II study.Gynecol Oncol,2009; 112(2):384-388.
Carrabin N, Mithieux F. Meeus P, et al. Hyperthermic intraperitoneal chemotherapy with oxaliplatin and without adjuvant chemotherapy in stage III С ovarian cancer. Bull Cancer,2010;97(4):10023-10032.
Krawczyk PM, Eppink B, Essers J, et al. Mild hyperthermia inhibits homologous recombination, induces BRCA2 degradation, and sensitizes cancer cells to poly (ADP-ribose) polymerase-1 inhibition. Proc Natl Acad Sci U S A, 2011; 08 (24);9851-9856.
Raaphorst GP, Yang DP. The evaluation of thermal cisplatin sensitization in normal and XP human cells using mild hyperthermia at 40 and 41 C. Anticancer Res, 2005; 25(4): 2649-2653.
Debes A, Willers R, Gobel U, et al. Role of heat treatment in childhood cancers: distinct resistance profiles of solid tumor cell lines towards combined thermochemotherapy. Pediatr Blood Cancer,2005;45(5):663-669.
Haveman J. Bergs JWJ, Franken NAP, et al. Effect of hyperthermia on uptake and cytotoxicity of cisplatin in cultured murine mammary carcinoma cells. Oncol Rep, 2005; 14(2): 561-567.
Istomin YP. Zhavrid EA, Sachivko NV, et al. The effect of cytostatics and hyperthermia on RAJ I human lymphoma cells. Exp Oncol,2011;33:19-23.
Istomin YP, Zhavrid EA, Alexandrova EN, et al. Dose enhancement effect of anticaner drugs associated with increased temperature in vitro. Exp Oncol,2008;30( 1):56-59.
Almeida GM, Duarte TL, Farmer PB. et al. Multiple end¬point analysis reveals cisplatin damage tolerance to be a chemoresistance mechanism in a NSCLC model: implications for predictive testing. Int J Cancer,2008; 122(8): 1810-1819.
Krivak TC, Darcy KM, Tian C, et al. Single nucleotide polypmorphisms in ERCC1 are associated with disease progression, and survival in patients with advanced stage ovarian and primary peritoneal carcinoma; a Gynecologic Oncology Group study. Gynecol Oncol, 2011; 122(1 ): 121- 126.
Moxley KM, Benbrook DM, Queimado L, et al. The role of single nucleotide polymorphisms of the ERCC1 and MMS19 genes in predicting platinum-sensitivity, progression-free and overall survival in advanced epithelial ovarian cancer. Gynecol Oncol,2013; 130(2) :377-382.
Rauch A, Hennig D, Schafer C, et al. Survivin and YM155; How faithful is the liaison. Biochim Biophys Acta, 2014; 1815 (2):202-220.
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