Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
BMC Cancer
Published in: BMC Cancer 1/2015

Open Access 01-12-2015 | Research article

Antihormonal agents as a strategy to improve the effect of chemo-radiation in cervical cancer: in vitro and in vivo study

Authors: Mariana Segovia-Mendoza, Rafael Jurado, Roser Mir, Luis A Medina, Heriberto Prado-Garcia, Patricia Garcia-Lopez

Published in: BMC Cancer | Issue 1/2015

Login to get access

Abstract

Background

Over the past few years, the concurrent use of cisplatin-based chemotherapy and radiation therapy has dramatically improved the local response and increased overall survival in early-stage cervical cancer. However, for the advanced stages of the disease this standard treatment has proved insufficient. We investigated the capacity of Mifepristone and ICI 182,780, which are anti-progestin and anti-estrogen drugs, respectively, to act as chemo-radiosensitizing agents in cervical cancer cells and cervix xenografts.

Methods

The effect of chemo-radiation alone or combined with Mifepristone or ICI 182,780 was evaluated in HeLa cells and with tumor growth in cervix xenografts. After concomitant chemo-radiotherapy, the effect of each of these antihormonal agents on apoptosis (determined by Annexing V assay) and the cell cycle phases were determined by flow cytometry. The expression of angiogenic factor VEGF in tumor samples was determined using quantitative RT-PCR analysis of VEGF gene expression.

Results

Compared to radiation alone or radiation/cisplatin therapy, there was significantly higher cytotoxicity and a greater antitumoral effect with the combined application of radiation/cisplatin and Mifepristone or ICI 182,780. Analyses of the apoptosis and cell cycle demonstrated changes only with ICI, not with Mifepristone, when was applied in combination with radiation/cisplatin. The analysis of VEGF mRNA expression levels in tumors at the end of the study demonstrated a significant inhibition, compared to radiation only or the radiation/cisplatin treatment, after concurrent chemo-radiotherapy and each one of the antihormonal drugs.

Conclusion

Mifepristone and ICI 182,780 may be potentially promising chemo-radiosensitizing compounds to be used in combination with ionizing irradiation and cisplatin in the treatment of patients with advanced cervical cancer.
Literature
1.
Bosch FX. Epidemiology of human papillomavirus infections: new options for cervical cancer prevention. Salud Publica Mex. 2003;45:S326–39.PubMed
2.
Lörincz AT. Screening for cervical cancer: new alternatives and research. Salud Publica Mex. 2003;45:S376–87.CrossRefPubMed
3.
Walboomers JM, Jacobs MV, Manos MM, Bosch FX, Kummer JA, Shah KV, et al. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol. 1999;189(1):12–9.CrossRefPubMed
4.
5.
Takashi N, Tatsuya O, Hitoshi I, Yoshiyuki S, Takeo T. Current advancement in radiation therapy for uterine cervical cancer. J Radiat Res. 2010;51:1–8.CrossRef
6.
Eifel PJ, Winter K, Morris M, Levenback C, Grigsby PW, Cooper J, et al. Pelvic irradiation with concurrent chemotherapy versus pelvic and para-aortic irradiation for high-risk cervical cancer. J Clin Oncol. 2004;22:872–80.CrossRefPubMed
7.
Morris M, Eifel PJ, Lu J, Grigsby PW, Levenback C, Stevens RE, et al. Pelvic radiation with concurrent chemotherapy compared with pelvic and para-aortic radiation for high-risk cervical cancer. N Engl J Med. 1999;340:1137–43.CrossRefPubMed
8.
Rose PG, Bundy BN, Watkins EB, Thigpen JT, Deppe G, Maiman MA, et al. Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer. N Engl J Med. 1999;340:1144–53.CrossRefPubMed
9.
Benedetti PP, Greggi S, Scambia G. High-dose cisplatin and bleomycin neoadjuvant chemotherapy plus radical surgery in locally advanced cervical carcinoma: a preliminary report. Gynecol Oncol. 1991;41:212.CrossRef
10.
Soutter WP, Leake RA. Steroid Hormone Receptors in Gynaecological Cancer. In: Bonnard J, editor. Recent Advances in Obstetrics and Gynaecology. Edinburgh: Churchill Livingstone; 1987. p. 175.
11.
Winston R, Kao PC, Kiang DT. Regulation of insulin-like growth factors by antiestrogen. Breast Cancer Res Treat. 1994;31(1):107–15.CrossRefPubMed
12.
Jain JK, Li A, Yang W, Minoo P, Felix JC. Effects of mifepristone on proliferation and apoptosis of human endometrium in new users of medroxyprogesterone acetate. Hum Reprod. 2006;21(3):798–809.CrossRefPubMed
13.
Ercoli A, Battaglia A, Raspaglio G, Fattorossi A, Alimonti A, Petrucci F, et al. Activity of cisplatin and ICI 182,780 on estrogen receptor negative ovarian cancer cells: cell cycle and cell replication rate perturbation, chromatin texture alteration and apoptosis induction. Int J Cancer. 2000;85(1):98–103.CrossRefPubMed
14.
Kamradt MC, Mohideen N, Vaughan AT. RU486 increases radiosensitivity and restores apoptosis through modulation of HPV E6/E7 in dexamethasone-treated cervical carcinoma cells. Gynecol Oncol. 2000;77(1):177–82.CrossRefPubMed
15.
Riggins RB, Bouton AH, Liu MC, Clarke R. Antiestrogens, aromatase inhibitors, and apoptosis in breast cancer. Vitam Horm. 2005;71:201–37.CrossRefPubMed
16.
Huang J, Zhang Y, Huang Y, Zhang X, Xiao J. Reversal effect of mifepristone on adriamycin resistance in human breast cancer cell line MCF-7/ADM in vitro and in vivo. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2010;35:576–83.PubMed
17.
Gamarra-Luques CD, Goyeneche AA, Hapon MB, Telleria CM. Mifepristone prevents repopulation of ovarian cancer cells escaping cisplatin-paclitaxel therapy. BMC Cancer. 2012;12:200.CrossRefPubMed
18.
Freeburg EM, Goyeneche AA, Telleria CM. Mifepristone abrogates repopulation of ovarian cancer cells in between courses of cisplatin treatment. Int J Oncol. 2009;34:743–55.PubMedPubMedCentral
19.
Jurado R, Lopez-Flores A, Alvarez A, Garcia-Lopez P. Cisplatin cytotoxicity is increased by mifepristone in cervical carcinoma: an in vitro and in vivo study. Oncol Rep. 2009;22:1237–45.PubMed
20.
Llaguno-Munive M, Medina LA, Jurado R, Romero-Pina M, Garcia-Lopez P. Mifepristone improves chemo-radiation response in glioblastoma xenografts. Cancer Cell Int. 2013;13:29.CrossRefPubMedPubMedCentral
21.
García-López P, Rodríguez-Dorantes M, Enrique Perez-Cardenas E, Cerbon M, Mohar-Betancourt A. Synergistic effects of ICI 182,780 on the cytotoxicity of cisplatin in cervical carcinoma cell lines. Cancer Chemother Pharmacol. 2004;53:533–40.CrossRefPubMed
22.
Munshi A, Hobbs M, Meyn RE. Clonogenic Cell survival Assay. In: Blumenthal RD, editor. Methods in Molecular Medicine. Volume 110: Chemosensitivity. 1st ed. Humana Press Inc: Totowa, New Jersey; 2005. p. 21–8.
23.
Medina LA, Herrera-Penilla BI, Castro-Morales MA, García-López P, Jurado R, Pérez-Cárdenas E, et al. Use of an orthovoltage X-ray treatment unit as a radiation research system in a small-animal cancer model. J Exp Clin Cancer Res. 2008;27:57.CrossRefPubMedPubMedCentral
24.
Kim KY, Seo JY, Jeon GA, Nam MJ. The combined treatment of aspirin and radiation induces apoptosis by the regulation of bcl-2 and caspase-3 in human cervical cancer cell. Cancer Lett. 2003;189(2):157–66.CrossRefPubMed
25.
Nair S, Nair RR, Srinivas P, Srinivas G, Pillai MR. Radiosensitizing effects of plumbagin in cervical cancer cells is through modulation of apoptotic pathway. Mol Carcinog. 2008;47(1):22–33.CrossRefPubMed
26.
Tillmanns TD, Kamelle SA, Guruswamy S, Gould NS, Rutledge TL, Benbrook DM. Sensitization of cervical cancer cell lines to low-dose radiation by retinoic acid does not require functional p53. Gynecol Oncol. 2005;97(1):142–50.CrossRefPubMed
27.
Lecureur V, Fardel O, Guillouzo A. The antiprogestatin drug RU 486 potentiates doxorubicin cytotoxicity in multidrug resistant cells through inhibition of P-glycoprotein function. FEBS Lett. 1994;355:187–91.CrossRefPubMed
28.
De Vicenzo R, Scambia G, Benedetti P, Fattorossi A, Bonanno G, Ferlini C, et al. Modulatory effect of tamoxifen and ICI 182,780 on adriamycin resistance in MCF-7 human breast-cancer cells. Int J Cancer. 1996;4(68(3)):340–8.CrossRef
29.
Goyeneche AA, Seidel EE, Telleria CM. Growth inhibition induced by antiprogestins RU-38486, ORG-31710, and CDB-2914 in ovarian cancer cells involves inhibition of cyclin dependent kinase 2. Invest New Drugs. 2012;30(3):967–80.CrossRefPubMed
30.
Liang Y, Hou M, Kallab AM, Barrett JT, El Etreby F, Schoenlein PV. Induction of antiproliferation and apoptosis in estrogen receptor negative MDA-231 human breast cancer cells by mifepristone and 4-hydroxytamoxifen combination therapy: a role for TGFbeta1. Int J Oncol. 2003;23:369–80.PubMed
31.
El Etreby MF, Liang Y, Wrenn RW, Schoenlein PV. Additive effect of mifepristone and tamoxifen on apoptotic pathways in MCF-7 human breast cancer cells. Breast Cancer Res Treat. 1998;51:149–68.CrossRefPubMed
32.
Rose FV, Barnea ER. Response of human ovarian carcinoma cell lines to antiprogestin mifepristone. Oncogene. 1996;12(5):999–1003.PubMed
33.
Rocereto TF, Saul HM, Aikins Jr JA, Paulson J. Phase II study of mifepristone (RU486) in refractory ovarian cancer. Gynecol Oncol. 2000;77:429–32.CrossRefPubMed
34.
Navo MA, Smith JA, Gaikwad A, Burke T, Brown J, Ramondetta LM. In vitro evaluation of the growth inhibition and apoptosis effect of mifepristone (RU486) in human Ishikawa and HEC1A endometrial cancer cell lines. Cancer Chemother Pharmacol. 2008;62:483–9.CrossRefPubMed
35.
Zhang H, Lu JJ, Gao QZ, Zhang J. Induction of apoptosis by mifepristone in androgen-independent prostate cancer cell lines in vitro. Zhonghua Wai Ke Za Zhi. 2006;44:382–5.PubMed
36.
Li DQ, Wang ZB, Bai J, Zhao J, Wang Y, Hu K. Effects of mifepristone on proliferation of human gastric adenocarcinoma cell line SGC-7901 in vitro. World J Gastroenterol. 2004;10:2628–31.CrossRefPubMedPubMedCentral
37.
Tieszen CR, Goyeneche AA, Brandhagen BN, Ortbahn CT, Telleria CM. Antiprogestin mifepristone inhibits the growth of cancer cells of reproductive and non-reproductive origin regardless of progesterone receptor expression. BMC Cancer. 2011;11:207.CrossRefPubMedPubMedCentral
38.
39.
Musgrove EA, Lee CS, Cornish AL, Swarbrick A, Sutherland RL. Antiprogestin inhibition of cell cycle progression in T-47D breast cancer cells is accompanied by induction of the cyclin-dependent kinase inhibitor p21. Mol Endocrinol. 1997;11:54–66.CrossRefPubMed
40.
Leblanc K, Sexton É, Parent S, Bélanger G, Déry M, Boucher V, et al. Effects of 4-hydroxytamoxifen, raloxifene and ICI 182 780 on survival of uterine cancer cell lines in the presence and absence of exogenous estrogens. Int J Oncol. 2007;30(2):477–87.PubMed
41.
Sun QL, Zhang XG, Xing QT, Ding P, Feng JB, Wu XP, et al. A study of mifepristone/IFN-γ-induced apoptosis of human cholangiocarcinoma cell line FRH-0201 in vitro. Onco Targets Ther. 2012;5:335–42.CrossRefPubMedPubMedCentral
42.
Gaddy V, Barret J, Delk J. Mifepristone induced growth arrest caspase activation and apoptosis of estrogen receptor expressing antiestrogen resistant breast cancer cell. Clin Cancer Res. 2004;10:5215–25.CrossRefPubMed
43.
Han S, Sidell N. RU 486 induced growth inthibition of human endometrial cells involves the nuclear factor kappa B signaling pathway. J Clin Endocrinol Metab. 2003;88:713–9.CrossRefPubMed
44.
Skor MN, Wonder EL, Kocherginsky M, Goyal A, Hall BA, Cai Y, et al. Glucocorticoid receptor antagonism as a novel therapy for triple-negative breast cancer. Clin Cancer Res. 2013;19:6163–72.CrossRefPubMed
45.
Fauvet R, Dufournet Etienne C, Poncelet C, Bringuier AF, Feldmann G, Darai E. Effects of progesterone and anti-progestin (mifepristone) treatment on proliferation and apoptosis of the human ovarian cancer cell line, OVCAR-3. Oncol Rep. 2006;15:743–8.PubMed
46.
Jang JH, Woo SM, Um HJ, Park EJ, Min KJ, Lee TJ, et al. RU486, a glucocorticoid receptor antagonist, induces apoptosis in U937 human lymphoma cells through reduction in mitochondrial membrane potential and activation of p38 MAPK. Oncol Rep. 2013;30:506–12.PubMed
47.
Fjelldal R, Moe BT, Orbo A, Sager G. MCF-7 cell apoptosis and cell cycle arrest: non-genomic effects of progesterone and mifepristone (RU-486). Anticancer Res. 2010;30:4835–40.PubMed
48.
Li C, Ye H. Mifepristone sensitizing cisplatin for cervical adenocarcinoma HeLa cell sensitivity to chemotherapy and its mechanism. Eur J Gynaecol Oncol. 2013;34:142–7.PubMed
49.
Homback N, Shen R, Shidnia H, Kaiser H. Synergistic cytotoxic and antitumor effects of irradiation and taxol on human HeLa cervix carcinoma and mouse B16 melanoma cells. In vivo. 1994;8(5):819–23.
50.
Liu C, Chang H, Chen I, Chen C, Hsu M, Ful S, et al. Costunolide causes mitotic arrest and enhances radiosensitivity in human hepatocellular carcinoma cells. Radiat Oncol. 2011;6:2–8.CrossRef
51.
Ikeda H, Taira N, Nogami T, Shien K, Okada M, Shien T, et al. Combination treatment with fulvestrant and various cytotoxic agents (doxorubicin, paclitaxel, docetaxel, vinorelbine, and 5-fluorouracil) has a synergistic effect in estrogen receptor-positive breast cancer. Cancer Sci. 2011;102(11):2038–42.CrossRefPubMed
52.
Giangrande PH, Pollio G, McDonnell DP. Mapping and characterization of the functional domains responsible for the differential activity of the A and B isoforms of the human progesterone receptor. J Biol Chem. 1997;272(52):32889–900.CrossRefPubMed
53.
McDonnell DP, Goldman ME. RU486 exerts antiestrogenic activities through a novel progesterone receptor A form-mediated mechanism. J Biol Chem. 1994;269(16):11945–9.PubMed
54.
Fontanini G, Boldrini L, Vignati S, Chinè S, Basolo F, Silvestri V, et al. Bcl2 and p53 regulate vascular endothelial growth factor (VEGF)-mediated angiogenesis in non-small cell lung carcinoma. Eur J Cancer. 1998;34(5):718–23.CrossRefPubMed
55.
56.
Samuel S, Fan F, Dang LH, Xia L, Gaur P, Ellis LM. Intracrine vascular endothelial growth factor signaling in survival and chemoresistance of human colorectal cancer cells. Oncogene. 2010;30(10):1205–12.CrossRefPubMedPubMedCentral
57.
Basith S, Manavalan B, Yoo TH, Kim SG, Choi S. Roles of toll-like receptors in cancer: a double-edged sword for defense and offense. Arch Pharm Res. 2012;35(8):1297–31.CrossRefPubMed
58.
Zhang Y, Yang H, Barnie PA, Yang P, Su Z, Chen J, et al. The expression of Toll-like receptor 8 and its relationship with VEGF and Bcl-2 in cervical cancer. Int J Med Sci. 2014;11(6):608–13.CrossRefPubMedPubMedCentral
Metadata
Title
Antihormonal agents as a strategy to improve the effect of chemo-radiation in cervical cancer: in vitro and in vivo study
Authors
Mariana Segovia-Mendoza
Rafael Jurado
Roser Mir
Luis A Medina
Heriberto Prado-Garcia
Patricia Garcia-Lopez
Publication date
01-12-2015
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2015
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-015-1016-4

Other articles of this Issue 1/2015

BMC Cancer 1/2015 Go to the issue

Research article

Gonadotropin-mediated chemoresistance: Delineation of molecular pathways and targets

Case report

Psychogenic fever in a patient with small cell lung cancer: a case report

Research article

DNA Polymerases as targets for gene therapy of hepatocellular carcinoma

Research article

Therapeutic effect of intravesical administration of paclitaxel solubilized with poly(2-methacryloyloxyethyl phosphorylcholine-co-n-butyl methacrylate) in an orthotopic bladder cancer model

Case report

Durable recurrence-free survival after pneumonectomy for late lung metastasis from rectal cancer: case report with genetic and epigenetic analyses

Research article

Number of negative lymph nodes is associated with disease-free survival in patients with breast cancer
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits