Octreotide is the favorable alternative for cisplatin resistance reversal of ovarian cancer in vitro and in nude mice in vivo

This study aimed to observe the effects of octreotide (OCT) on cisplatin resistance reversal of cancer cells in vitro and in nude mice in vivo. MTT method and flow cytometry were used to investigate the effect of cisplatin, OCT or the combination of these two compounds on the proliferation and apoptosis of SKOV3-DDP cells. The size and weight of xenograft tumors from the nude mice model were measured. Real-time PCR was used to detect the mRNA expression of SSTR2, MDR1, MRP2, GST-pi and EGFR in SKOV3/DDP cells following the different treatment. At the concentration of 2.5-20 g/ml, OCT significantly reduced IC50 (p < 0.05) and promoted apoptosis (p < 0.05) of SKOV3-DDP cells' response to cisplatin. Unchanged expression was found in SSTR2 on the SKOV3/DDP cell in vitro after OCT treatment, but increased expression in vivo (p < 0.05). OCT increased GST-pi expression (p < 0.05) and reduced MRP2 and EGFR expression (p < 0.05) in a dose-dependent manner. The similar results were obtained in mice in vivo experiment, except the reduced expression of GST-pi. It is suggested that OCT could inhibit ovarian cancer proliferation and promote apoptosis, via the cell surface SSTR2, and reverse cisplatin resistance through inhibition of MRP2, EGFR, and even GST-pi expressions.

Octreotide; Somatostatin; Epithelial ovarian cancer; Resistance reversal

[1] Posadas E.M., Davidson B., Kohn E.C.: “Proteomics and ovarian cancer: implications for diagnosis and treatment: a critical review the recent literature”. Curr. Opin. Oncol., 2004, 16, 478.

[2] Yakirevich E., Sabo E., Naroditsky I., Sova Y., Lavie O., Resnick M.B.: “Multidrug resistance-related henotype and apoptosis-related protein expression in ovarian serous carcinomas”. Gynecol. Oncol., 2006, 100, 152.

[3] Halmos G., Sun B., Schally A.V., Hebert F., Nagy A.: “Human ovarian cancers express somatostatin receptors”. J. Clin. Endo crinol. Metab., 2000, 85, 3509.

[4] Hall G.H., Turnbull L.W., Richmond I., Helboe L., Atkin S.L.: “Localisation of somatostatin and somatostatin receptors in benign and malignant ovarian tumours”. Br. J. Cancer, 2002, 87, 86.

[5] Qin Y.Y., Li J.Y., Li S.G., Yue J.N., Quan Z.W.: “[Mechanism research in somatostatin reverting the chemosensitivity of GBCSD cell line]”. Zhonghua Wai Ke Za Zhi, 2008, 46, 381.

[6] Pyronnet S., Bousquet C., Najib S., Azar R., Laklai H., Susini C.: “Antitumor effects of somatostatin”. Mol. Cell. Endocrinol., 2008, 286, 230.

[7] Robbins R.J.: “Somatostatin and cancer”. Metabolism, 1996, 45, 98.

[8] Guillermet-Guibert J., Lahlou H., Cordelier P., Bousquet C., Pyronnet S., Susini C.: “Physiology of somatostatin receptors”. J. Endocrinol. Invest., 2005, 28, 5.

[9] Vernejoul F., Faure P., Benali N., Calise D., Tiraby G., Pradayrol L. et al.: “Antitumor effect of in vivo somatostatin receptor subtype 2 gene transfer in primary and metastatic pancreatic cancer models”. Cancer Res., 2002, 62, 6124.

[10] Samonakis D.N., Moschandreas J., Arnaoutis T., Skordilis P., Leontidis C., Vafiades I., Kouroumalis E.: “Treatment of hepatocellular carcinoma with long acting somatostatin analogues”. Oncol. Rep., 2002, 9, 903.

[11] Behrens B.C., Hamilton T.C., Masuda H., Grotzinger K.R., Whang-Peng J., Louie K.G. et al.: “Characterization of a cisdiamminedichloroplatinum(II)-resistant human ovarian cancer cell line and its use in evaluation of platinum analogues”. Cancer Res., 1997, 47, 414.

[12] Jones R.H., Reubi J.C., Millan D., Vasey P.: “Octreotide: an active agent in epithelial ovarian carcinoma?”. Lancet Oncol., 2004, 5, 251.

[13] Barnett P.: “Somatostatin and somatostatin receptor physiology”. Endocrine, 2003, 20, 255.

[14] Li M., Li W., Kim H.J., Yao Q., Chen C., Fisher W.E.: “Characterization of somatostatin receptor expression in human pancreatic cancer using real-time RT-PCR”. J. Surg. Res., 2004, 119, 130.

[15] Murphy E., Prommer E., Mihalyo M.: “Octreotide”. J. Pain. Symptom. Manage, 2010, 40, 142.

[16] Hua Y.P., Yin X.Y., Peng B.G., Li S.Q., Lai J.M., Liang H.Z., Liang L.J.: “Mechanisms and influence of octreotide-induced regulation of somatostatin receptor 2 on hepatocellular carcinoma”. Chemotherapy, 2009, 55, 312.

[17] Gabriel M., Andergassen U., Putzer D., Kroiss A., Waitz D., Von Guggenberg E. et al.: “Individualized peptide-related-radionuclide-therapy concept using different radiolabelled somatostatin analogs in advanced cancer patients”. Q.J. Nucl. Med. Mol. Imaging, 2010, 54, 92.

[18] Diaconu C.C., Szathmari M., Keri G., Venetianer A.: “Apoptosis is induced in both drug-sensitive and multidrug-resistant hepatoma cells by somatostatin analogue TT-232”. Br. J. Cancer, 1999, 80, 1197.

[19] Ma J.J., Chen B.L., Xin X.Y.: “Inhibition of multidrug resistance of ovarian carcinoma by small interfering RNA targeting to MRP2 gene”. Arch. Gynecol. Obstet., 2009, 279, 149.

[20] Surowiak P., Materna V., Kaplenko I., Spaczynski M., Dolinska- Krajewska B., Gebarowska E. et al.: “ABCC2 (MRP2, cMOAT) can be localized in the nuclear membrane of ovarian carcinomas and correlates with resistance to cisplatin and clinical outcome”. Clin. Cancer Res., 2006, 12, 7149.

[21] Park S.J., Armstrong S., Kim C.H., Yu M., Robertson K., Kelley M.R., Lee S.H.: “Lack of EGF receptor contributes to drug sensitivity of human germline cells”. Br. J. Cancer, 2005, 92, 334.

[22] Chan J.K., Pham H., You X.J., Cloven N.G., Burger R.A., Rose G.S. et al.: “Suppression of ovarian cancer cell tumorigenicity and evasion of Cisplatin resistance using a truncated epidermal growth factor receptor in a rat model”. Cancer Res., 2005, 65, 3243.

[23] Mishima M., Yano T., Jimbo H., Yano N., Morita Y., Yoshikawa H. et al.: “Inhibition of human endometrial cancer cell growth in vitro and in vivo by somatostatin analog RC-160”. Am. J. Obstet. Gynecol., 1999, 181, 583.

[24] Kang E.S., Oh M.A., Lee S.A., Kim T.Y., Kim S.H., Gotoh N.: “EGFR phosphorylation-dependent formation of cell-cell contacts by Ras/Erks cascade inhibition”. Biochim. Biophys. Acta, 2007, 1773, 833.

[25] Ghalia A.A., Rabboh N.A., el Shalakani A., Seada L., Khalifa A.: “Estimation of glutathione S-transferase and its Pi isoenzyme in tumor tissues and sera of patients with ovarian cancer”. Anticancer Res., 2000, 20, 1229.

[26] Vanhoefer U., Yin M.B., Harstrick A., Seeber S., Rustum Y.M.: “Carbamoylation of glutathione reductase by N,N-bis(2- chloroethyl)-N- nitrosourea associated with inhibition of multidrug resistance protein (MRP) function”. Biochem. Pharmacol., 1997, 53, 801.

[27] Lukyanova N.Y.: “Characteristics of homocysteine-induced multidrug resistance of human MCF-7 breast cancer cells and human A2780 ovarian cancer cells”. Exp. Oncol., 2010, 32, 10.

[28] Schondorf T., Kurbacher C.M., Gohring U.J., Benz C., Becker M., Sartorius J. et al.: “Induction of MDR1-gene expression by antineoplastic agents in ovarian cancer cell lines”. Anticancer Res., 2002, 22, 2199.