Insulin in endometrial carcinoma chemotherapy: A beneficial addition and not a problem

Abstract

The effects of insulin or insulin in combination with chemotherapeutic drugs on the proliferation and apoptosis of endometrial carcinoma cells were examined with an aim to determine the efficacy and safety of insulin in endometrial cancer therapy. Ishikawa and Hec-1A cells were treated with insulin and/or paclitaxel. Cell proliferation was assessed by MTT assay. Cell cycle and cell apoptosis were determined by flow cytometry (FCM). Survivin gene expression was detected by RT-PCR. Our results showed that in a certain range of working concentrations and action time, insulin could mildly augment cell proliferation and the percentage of S phase cells in endometrial cancer (Ishikawa/Hec-1A) cells. Insulin plus paclitaxel (combination group) could significantly inhibit cell proliferation (69.38%±2.32% vs 40.31%±4.52% with Ishikawa; 64.11%±6.33% vs 45.89%±3.27% with Hec-1A) and increase cell apoptosis compared with treatment with paclitaxel alone (paclitaxel group). Survivin gene expression was also significantly decreased in combination group as compared with paclitaxel group. We are led to conclude that insulin can mildly augment cell proliferation and present chemotherapy sensitivity in endometrial cancer cells. Insulin can be to used safely and efficiently in endometrial cancer therapy.

Keywords

insulin / chemotherapy sensitivity / endometrial cancer / apoptosis / proliferation / cell cycle / survivin

References

[1] American Cancer Society. Cancer Facts & Figures 2006. American Cancer Society, 2006

[2] ShiozawaT., KonishiI.. Early endometrial carcinoma: clinicopathology, hormonal aspects, moleculargenetics, diagnosis, and treatment. Int J Clin Oncol, 2006, 11(1): 13-21

[3] SaltzmanB.S., DohertyJ.A., HillD.A., et al.. Diabetes and endometrial cancer: An evaluation of the modifying effects of other known risk factors. Am J Epidemiol, 2008, 167(5): 607-614

[4] PisaniP.. Hyper-insulinaemia and cancer, meta-analyses of epidemiological studies. Arch Physiol Biochem, 2008, 114(1): 63-70

[5] ZhaoJ., XueF.X., HuaS.F., et al.. Effects of insulin on proliferation and apoptosis of endometrial carcinoma cell. Zhonghua Fu Chan Ke Za Zhi (Chinese), 2007, 42(10): 696-700

[6] AlabasterO., VonderharrB.K., ShafieS.M.. Metabolic modification by insulin enhances methotrexate cytoxicity in MCF-7 human breast cancer cells. Eur J Cancer Clin Oncol, 1981, 17(11): 1223-1228

[7] MigliettaA., PannoM.L., BozzoF., et al.. Insulin can modulate MCF-7 cell response to paelitaxel. Cancer Lett, 2004, 209(2): 139-45

[8] AyreS.G., Garcia y BellonD.P., GarciaD.P.Jr., et al.. Insulin, chemotherapy, and the mechanisms of malignancy: the design and the demise of cancer. Med Hypotheses, 2000, 55(4): 330-334

[9] TangjitgamolS., AndersonB.O., SeeH.T., et al.. Management of endometrial cancer in Asia: consensus statement from the Asian Oncology Summit 2009. Lancet Oncol, 2009, 10(11): 1119-1127

[10] AokiY., WatanabeM., AmikuraT., et al.. Adjuvant chemotherapy as treatment of high-risk stage I and II endometrial cancer. Gynecol Oncol, 2004, 94(2): 333-339

[11] ShackneyS.E., McCormackG.W., CocheralG.J.. Growth rate patterns of solid tumors and their relation to responsiveness to therapy. Ann Intern Med, 1978, 89(1): 107-121

[12] GulloC., KohL.K., PangW.L., et al.. Inhibition of proliferation and induction of apoptosis in multiple myeloma cell lines by CD137 ligand signaling. PLoS One, 2010, 5(5): e10845

[13] van BrusselJ.P., OomenM.A., VossebeldP.J., et al.. Identification of multidrug resistance-associated protein 1 and glutathione as multidrug resistance mechanisms in human prostate cancer cells: chemosensitization with leukotriene D4 antagonists and buthionine sulfoximine. BJU Int, 2004, 93(9): 1333-1338

[14] NagamaniM., StuartC.A.. Specific binding and growth-promoting activity of insulin in endometrial cancer cells in culture. Am J Obstet Gynecol, 1998, 179(1): 6-12

[15] MutiP., QuattrinT., GrantB.J., et al.. Fasting glucose is a risk factor for breast cancer: a prospective study. Cancer Epidemiol. Biomarkers Prev, 2002, 11(11): 1361-1368

[16] MonacoS., IllarioM., RuscianoM.R., et al.. Insulin stimulates fibroblast proliferation through calcium-calmodulin-dependent kinase II. Cell Cycle., 2009, 8(13): 2024-30

[17] BelfioreA.. The role of insulin receptor isoforms and hybrid insulin/IGF-I receptors in human cancer. Curr Pharm Des, 2007, 13(7): 671-686

[18] GoodwinP.J., EnnisM., PritchardK.I., et al.. Fasting insulin and outcome in early-stage breast cancer: results of a prospective cohort study. J Clin Oncol, 2002, 20(1): 42-51

[19] GiovannucciE.. Metabolic syndrome, hyperinsulinemia, and colon cancer: a review. Am J Clin Nutr, 2007, 86(3): s836-s842

[20] NordsmarkM., OvergaardJ.. A confirmatory prognostic study on oxygenation status and loco-regional control in advanced head and neck squamous cell carcinoma treated by radiation therapy. Radiother Oncol, 2000, 57(1): 39-43

[21] JordanB.F., GrégoireV., DemeureR.J., et al.. Insulin increases the sensitivity of tumors to irradiation: involvement of an increase in tumor oxygenation mediated by a nitric oxide-dependent decrease of the tumor cells oxygen consumption. Cancer Res, 2002, 62(12): 3555-3561

[22] JordanB.F., BegheinN., CrokartN., et al.. Preclinical safety and antitumor efficacy of insulin combined with irradiation. Radiother Oncol, 2006, 81(1): 112-117

[23] JeffcoatR., JameA.T.. NumaS.. The regulation of desaturation and elongation of fatty acids in mammals. Fatty Acid Metabolism and its Regulation, 1984, Amsterdam, Elsevier Science Publishers, 85-112

[24] SrinivasulaS.M., AshwellJ.D.. IAPs: what’s in a name?. Mol Cell, 2008, 30(2): 123-135

[25] ZhangM., MukherjeeN., BermudezR.S., et al.. Adenovirus-mediated inhibition of survivin expression sensitizes human prostate cancer cells to paclitaxel in vitro and in vivo. Prostate, 2005, 64(3): 293-302

[26] PennatiM., FoliniM., ZaffaroniN.. Targeting survivin in cancer therapy: fulfilled promises and open questions. Carcinogenesis, 2007, 28(6): 1133-1139

[27] GuhaM., AltieriD.C.. Survivin as a global target of intrinsic tumor suppression networks. Cell Cycle, 2009, 8(17): 2708-2710

[28] TakaiN., MiyazakiT., NishidaM., et al.. Survivin expression correlates with clinical stage, histological grade, invasive behavior and survival rate in endometrial carcinoma. Cancer Lett, 2002, 184(1): 105-116