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Published in: Medical Oncology 6/2021

01-06-2021 | Endometrial Cancer | Original Paper

Preliminary evaluation on the beneficial effects of pioglitazone in the treatment of endometrial cancer

Authors: Garikapati Kusuma Kumari, Ammu V. V. V. Ravi Kiran, Praveen T. Krishnamurthy

Published in: Medical Oncology | Issue 6/2021

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Abstract

Endometrial cancer (EMC) is one of the complicated gynecological cancers, affecting more than three million women worldwide. Anticancer strategies such as chemotherapy, radiation, and surgery are found to be ineffective and are associated with patient incompliances. The aim of the present study is to repurpose non-oncological drug, i.e., Pioglitazone, a peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist, in the treatment of endometrial cancer. The study groups consist of 50 female Swiss albino mice, out of which 40 had endometrial cancer induced with N-ethyl-N-nitrosourea (ENU) and estradiol hexadrobenzoate (EHB). The other groups received saline, EHB, paclitaxel, and different test doses of pioglitazones. Different preliminary parameters such as weekly body weight, mean survival time, percentage increase in life span, and uterine tissue weight were analyzed along with histopathological analysis. We observed a significant change in weekly body weight, improvement in percentage life span, and partial restoration of uterine tissue weight to normal compared to a standard drug, paclitaxel. In the present preliminary evaluation, we have identified that pioglitazone exhibited a significant dose-dependent anticancer activity against ENU- and EHB-induced endometrial cancer, compared to the standard paclitaxel.
Literature
2.
go back to reference Ali AT. Risk factors for endometrial cancer. Ceska Gynekol. 2013;78:448–59.PubMed Ali AT. Risk factors for endometrial cancer. Ceska Gynekol. 2013;78:448–59.PubMed
3.
go back to reference MacMahon B. Risk factors for endometrial cancer. Gynecol Oncol. 1974;2:122–9.CrossRef MacMahon B. Risk factors for endometrial cancer. Gynecol Oncol. 1974;2:122–9.CrossRef
4.
go back to reference Brinton LA, Berman ML, Mortel R, Twiggs LB, Barrett RJ, Wilbanks GD, et al. Reproductive, menstrual, and medical risk factors for endometrial cancer: results from a case-control study. Am J Obstet Gynecol. 1992;167:1317–25.CrossRef Brinton LA, Berman ML, Mortel R, Twiggs LB, Barrett RJ, Wilbanks GD, et al. Reproductive, menstrual, and medical risk factors for endometrial cancer: results from a case-control study. Am J Obstet Gynecol. 1992;167:1317–25.CrossRef
5.
go back to reference Risk factors for endometrial cancer at different ages2. J Natl Cancer Inst [Internet]. 1984 [cited 2020 Oct 8]. Available from: https://academic.oup.com/jnci/article-lookup/doi/https://doi.org/10.1093/jnci/73.3.667 Risk factors for endometrial cancer at different ages2. J Natl Cancer Inst [Internet]. 1984 [cited 2020 Oct 8]. Available from: https://​academic.​oup.​com/​jnci/​article-lookup/​doi/​https://​doi.​org/​10.​1093/​jnci/​73.​3.​667
7.
go back to reference Dossus L, Allen N, Kaaks R, Bakken K, Lund E, Tjonneland A, et al. Reproductive risk factors and endometrial cancer: the European prospective investigation into cancer and nutrition. Int J Cancer. 2010;127(2):442–51.PubMed Dossus L, Allen N, Kaaks R, Bakken K, Lund E, Tjonneland A, et al. Reproductive risk factors and endometrial cancer: the European prospective investigation into cancer and nutrition. Int J Cancer. 2010;127(2):442–51.PubMed
10.
go back to reference Wu W, Celestino J, Milam MR, Schmeler KM, Broaddus RR, Ellenson LH, et al. Primary chemoprevention of endometrial hyperplasia with the peroxisome proliferator-activated receptor gamma agonist rosiglitazone in the PTEN heterozygote murine model. Int J Gynecol Cancer. 2008;18:329–38.CrossRef Wu W, Celestino J, Milam MR, Schmeler KM, Broaddus RR, Ellenson LH, et al. Primary chemoprevention of endometrial hyperplasia with the peroxisome proliferator-activated receptor gamma agonist rosiglitazone in the PTEN heterozygote murine model. Int J Gynecol Cancer. 2008;18:329–38.CrossRef
11.
go back to reference Djordjevic B, Hennessy BT, Li J, Barkoh BA, Luthra R, Mills GB, et al. Clinical assessment of PTEN loss in endometrial carcinoma: immunohistochemistry outperforms gene sequencing. Mod Pathol. 2012;25:699–708.CrossRef Djordjevic B, Hennessy BT, Li J, Barkoh BA, Luthra R, Mills GB, et al. Clinical assessment of PTEN loss in endometrial carcinoma: immunohistochemistry outperforms gene sequencing. Mod Pathol. 2012;25:699–708.CrossRef
12.
go back to reference Catasus L, Gallardo A, Cuatrecasas M, Prat J. Concomitant PI3K–AKT and p53 alterations in endometrial carcinomas are associated with poor prognosis. Mod Pathol. 2009;22:522–9.CrossRef Catasus L, Gallardo A, Cuatrecasas M, Prat J. Concomitant PI3K–AKT and p53 alterations in endometrial carcinomas are associated with poor prognosis. Mod Pathol. 2009;22:522–9.CrossRef
13.
go back to reference Tseng C-H. Metformin and endometrial cancer risk in Chinese women with type 2 diabetes mellitus in Taiwan. Gynecol Oncol. 2015;138:147–53.CrossRef Tseng C-H. Metformin and endometrial cancer risk in Chinese women with type 2 diabetes mellitus in Taiwan. Gynecol Oncol. 2015;138:147–53.CrossRef
14.
go back to reference Laskov I, Drudi L, Beauchamp M-C, Yasmeen A, Ferenczy A, Pollak M, et al. Anti-diabetic doses of metformin decrease proliferation markers in tumors of patients with endometrial cancer. Gynecol Oncol. 2014;134:607–14.CrossRef Laskov I, Drudi L, Beauchamp M-C, Yasmeen A, Ferenczy A, Pollak M, et al. Anti-diabetic doses of metformin decrease proliferation markers in tumors of patients with endometrial cancer. Gynecol Oncol. 2014;134:607–14.CrossRef
15.
go back to reference Wallbillich JJ, Josyula S, Saini U, Zingarelli RA, Dorayappan KDP, Riley MK, et al. High glucose-mediated STAT3 activation in endometrial cancer is inhibited by metformin: therapeutic implications for endometrial cancer. PLoS ONE. 2017;12:0170318.CrossRef Wallbillich JJ, Josyula S, Saini U, Zingarelli RA, Dorayappan KDP, Riley MK, et al. High glucose-mediated STAT3 activation in endometrial cancer is inhibited by metformin: therapeutic implications for endometrial cancer. PLoS ONE. 2017;12:0170318.CrossRef
16.
go back to reference Jin Z, Wu X, Liu H, Xu C. Celecoxib, a selective COX‑2 inhibitor, markedly reduced the severity of tamoxifen‑induced adenomyosis in a murine model. Exp Ther Med [Internet]. 2020 [cited 2020 Oct 22]. Available from: http://www.spandidos-publications.com/https://doi.org/10.3892/etm.2020.8580 Jin Z, Wu X, Liu H, Xu C. Celecoxib, a selective COX‑2 inhibitor, markedly reduced the severity of tamoxifen‑induced adenomyosis in a murine model. Exp Ther Med [Internet]. 2020 [cited 2020 Oct 22]. Available from: http://​www.​spandidos-publications.​com/​https://​doi.​org/​10.​3892/​etm.​2020.​8580
17.
go back to reference Almendros I, Gileles-Hillel A, Khalyfa A, Wang Y, Zhang SX, Carreras A, et al. Adipose tissue macrophage polarization by intermittent hypoxia in a mouse model of OSA: effect of tumor microenvironment. Cancer Lett. 2015;361:233–9.CrossRef Almendros I, Gileles-Hillel A, Khalyfa A, Wang Y, Zhang SX, Carreras A, et al. Adipose tissue macrophage polarization by intermittent hypoxia in a mouse model of OSA: effect of tumor microenvironment. Cancer Lett. 2015;361:233–9.CrossRef
19.
go back to reference Jasinski-Bergner S, Kielstein H. Adipokines regulate the expression of tumor-relevant MicroRNAs. Obes Facts. 2019;12:211–25.CrossRef Jasinski-Bergner S, Kielstein H. Adipokines regulate the expression of tumor-relevant MicroRNAs. Obes Facts. 2019;12:211–25.CrossRef
21.
go back to reference Howe LR, Subbaramaiah K, Hudis CA, Dannenberg AJ. Molecular pathways: adipose inflammation as a mediator of obesity-associated cancer. Clin Cancer Res. 2013;19:6074–83.CrossRef Howe LR, Subbaramaiah K, Hudis CA, Dannenberg AJ. Molecular pathways: adipose inflammation as a mediator of obesity-associated cancer. Clin Cancer Res. 2013;19:6074–83.CrossRef
22.
go back to reference Garikapati KK, Ammu VVVRK, Krishnamurthy PT, Chintamaneni PK, Pindiprolu SKSS. Type-II endometrial cancer: role of adipokines. Arch Gynecol Obstet. 2019;300:239–49.CrossRef Garikapati KK, Ammu VVVRK, Krishnamurthy PT, Chintamaneni PK, Pindiprolu SKSS. Type-II endometrial cancer: role of adipokines. Arch Gynecol Obstet. 2019;300:239–49.CrossRef
23.
go back to reference Ashizawa N, Yahata T, Quan J, Adachi S, Yoshihara K, Tanaka K. Serum leptin–adiponectin ratio and endometrial cancer risk in postmenopausal female subjects. Gynecol Oncol. 2010;119:65–9.CrossRef Ashizawa N, Yahata T, Quan J, Adachi S, Yoshihara K, Tanaka K. Serum leptin–adiponectin ratio and endometrial cancer risk in postmenopausal female subjects. Gynecol Oncol. 2010;119:65–9.CrossRef
24.
go back to reference Petridou E, Belechri M, Dessypris N, Koukoulomatis P, Diakomanolis E, Spanos E, et al. Leptin and body mass index in relation to endometrial cancer risk. Ann Nutr Metab. 2002;46:147–51.CrossRef Petridou E, Belechri M, Dessypris N, Koukoulomatis P, Diakomanolis E, Spanos E, et al. Leptin and body mass index in relation to endometrial cancer risk. Ann Nutr Metab. 2002;46:147–51.CrossRef
25.
go back to reference Nergiz Avcioglu S, Altinkaya SO, Küçük M, Yüksel H, Ömürlü IK, Yanik S. Visfatin concentrations in patients with endometrial cancer. Gynecol Endocrinol. 2015;31:202–7.CrossRef Nergiz Avcioglu S, Altinkaya SO, Küçük M, Yüksel H, Ömürlü IK, Yanik S. Visfatin concentrations in patients with endometrial cancer. Gynecol Endocrinol. 2015;31:202–7.CrossRef
26.
go back to reference Erdogan S, Sezer S, Baser E, Gun-Eryilmaz O, Gungor T, Uysal S, et al. Evaluating vaspin and adiponectin in postmenopausal women with endometrial cancer. Endocr Relat Cancer. 2013;20:669–75.CrossRef Erdogan S, Sezer S, Baser E, Gun-Eryilmaz O, Gungor T, Uysal S, et al. Evaluating vaspin and adiponectin in postmenopausal women with endometrial cancer. Endocr Relat Cancer. 2013;20:669–75.CrossRef
27.
go back to reference Chen M-P, Chung F-M, Chang D-M, Tsai JC-R, Huang H-F, Shin S-J, et al. Elevated plasma level of Visfatin/Pre-B cell colony-enhancing Factor in patients with type 2 diabetes mellitus. J Clin Endocrinol Metab. 2006;91:295–9.CrossRef Chen M-P, Chung F-M, Chang D-M, Tsai JC-R, Huang H-F, Shin S-J, et al. Elevated plasma level of Visfatin/Pre-B cell colony-enhancing Factor in patients with type 2 diabetes mellitus. J Clin Endocrinol Metab. 2006;91:295–9.CrossRef
28.
go back to reference Yamauchi T, Kamon J, Waki H, Terauchi Y, Kubota N, Hara K, et al. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med. 2001;7:941–6.CrossRef Yamauchi T, Kamon J, Waki H, Terauchi Y, Kubota N, Hara K, et al. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med. 2001;7:941–6.CrossRef
29.
go back to reference Petridou E, Mantzoros C, Dessypris N, Koukoulomatis P, Addy C, Voulgaris Z, et al. Plasma adiponectin concentrations in relation to endometrial cancer: a case-control study in Greece. J Clin Endocrinol Metab. 2003;88:993–7.CrossRef Petridou E, Mantzoros C, Dessypris N, Koukoulomatis P, Addy C, Voulgaris Z, et al. Plasma adiponectin concentrations in relation to endometrial cancer: a case-control study in Greece. J Clin Endocrinol Metab. 2003;88:993–7.CrossRef
30.
go back to reference Holland WL, Miller RA, Wang ZV, Sun K, Barth BM, Bui HH, et al. Receptor-mediated activation of ceramidase activity initiates the pleiotropic actions of adiponectin. Nat Med. 2011;17:55–63.CrossRef Holland WL, Miller RA, Wang ZV, Sun K, Barth BM, Bui HH, et al. Receptor-mediated activation of ceramidase activity initiates the pleiotropic actions of adiponectin. Nat Med. 2011;17:55–63.CrossRef
31.
go back to reference Garikapati KK, Ammu VVVRK, Krishnamurthy PT, Chintamaneni PK, Pindiprolu S, Kiran SS. Possible role of thiazolidinedione in the management of type-II endometrial cancer. Med Hypotheses. 2019;126:78–81.CrossRef Garikapati KK, Ammu VVVRK, Krishnamurthy PT, Chintamaneni PK, Pindiprolu S, Kiran SS. Possible role of thiazolidinedione in the management of type-II endometrial cancer. Med Hypotheses. 2019;126:78–81.CrossRef
32.
go back to reference Choi KC, Ryu OH, Lee KW, Kim HY, Seo JA, Kim SG, et al. Effect of PPAR-α and -γ agonist on the expression of visfatin, adiponectin, and TNF-α in visceral fat of OLETF rats. Biochem Biophys Res Commun. 2005;336:747–53.CrossRef Choi KC, Ryu OH, Lee KW, Kim HY, Seo JA, Kim SG, et al. Effect of PPAR-α and -γ agonist on the expression of visfatin, adiponectin, and TNF-α in visceral fat of OLETF rats. Biochem Biophys Res Commun. 2005;336:747–53.CrossRef
33.
34.
go back to reference Hammarstedt A, Andersson CX, Rotter Sopasakis V, Smith U. The effect of PPARγ ligands on the adipose tissue in insulin resistance. Prostaglandins Leukot Essent Fatty Acids. 2005;73:65–75.CrossRef Hammarstedt A, Andersson CX, Rotter Sopasakis V, Smith U. The effect of PPARγ ligands on the adipose tissue in insulin resistance. Prostaglandins Leukot Essent Fatty Acids. 2005;73:65–75.CrossRef
35.
go back to reference Aljada A, O’Connor L, Fu Y-Y, Mousa SA. PPARγ ligands, rosiglitazone and pioglitazone, inhibit bFGF- and VEGF-mediated angiogenesis. Angiogenesis. 2008;11:361–7.CrossRef Aljada A, O’Connor L, Fu Y-Y, Mousa SA. PPARγ ligands, rosiglitazone and pioglitazone, inhibit bFGF- and VEGF-mediated angiogenesis. Angiogenesis. 2008;11:361–7.CrossRef
36.
go back to reference Mahmoud MF, El Shazly SM. Pioglitazone protects against cisplatin induced nephrotoxicity in rats and potentiates its anticancer activity against human renal adenocarcinoma cell lines. Food Chem Toxicol. 2013;51:114–22.CrossRef Mahmoud MF, El Shazly SM. Pioglitazone protects against cisplatin induced nephrotoxicity in rats and potentiates its anticancer activity against human renal adenocarcinoma cell lines. Food Chem Toxicol. 2013;51:114–22.CrossRef
37.
go back to reference Lutchman G, Promrat K, Kleiner DE, Heller T, Ghany MG, Yanovski JA, et al. Changes in serum adipokine levels during pioglitazone treatment for nonalcoholic steatohepatitis: relationship to histological improvement. Clin Gastroenterol Hepatol. 2006;4:1048–52.CrossRef Lutchman G, Promrat K, Kleiner DE, Heller T, Ghany MG, Yanovski JA, et al. Changes in serum adipokine levels during pioglitazone treatment for nonalcoholic steatohepatitis: relationship to histological improvement. Clin Gastroenterol Hepatol. 2006;4:1048–52.CrossRef
38.
go back to reference Miyazawa M, Subbaramaiah K, Bhardwaj P, Zhou XK, Wang H, Falcone DJ, et al. Pioglitazone inhibits periprostatic white adipose tissue inflammation in obese mice. Cancer Prev Res. 2018;11:215–26.CrossRef Miyazawa M, Subbaramaiah K, Bhardwaj P, Zhou XK, Wang H, Falcone DJ, et al. Pioglitazone inhibits periprostatic white adipose tissue inflammation in obese mice. Cancer Prev Res. 2018;11:215–26.CrossRef
39.
go back to reference Gastaldelli A, Harrison S, Belfort-Aguiar R, Hardies J, Balas B, Schenker S, et al. Pioglitazone in the treatment of NASH: the role of adiponectin: role of adiponectin in NASH. Aliment Pharmacol Ther. 2010;32:769–75.CrossRef Gastaldelli A, Harrison S, Belfort-Aguiar R, Hardies J, Balas B, Schenker S, et al. Pioglitazone in the treatment of NASH: the role of adiponectin: role of adiponectin in NASH. Aliment Pharmacol Ther. 2010;32:769–75.CrossRef
40.
go back to reference Szychowski KA, Leja ML, Kaminskyy DV, Kryshchyshyn AP, Binduga UE, Pinyazhko OR, et al. Anticancer properties of 4-thiazolidinone derivatives depend on peroxisome proliferator-activated receptor gamma (PPARγ). Eur J Med Chem. 2017;141:162–8.CrossRef Szychowski KA, Leja ML, Kaminskyy DV, Kryshchyshyn AP, Binduga UE, Pinyazhko OR, et al. Anticancer properties of 4-thiazolidinone derivatives depend on peroxisome proliferator-activated receptor gamma (PPARγ). Eur J Med Chem. 2017;141:162–8.CrossRef
41.
go back to reference Takahashi M, Lijima T, Suzuki K, Ando-Lu J, Yoshida M, Kitamura T, et al. Rapid and high yield induction of endometrial adenocarcinomas in CD-1 mice by a single intrauterine administration of N-ethyl-N-nitrosourea combined with chronic 17β-estradiol treatment. Cancer Lett. 1996;104:7–12.CrossRef Takahashi M, Lijima T, Suzuki K, Ando-Lu J, Yoshida M, Kitamura T, et al. Rapid and high yield induction of endometrial adenocarcinomas in CD-1 mice by a single intrauterine administration of N-ethyl-N-nitrosourea combined with chronic 17β-estradiol treatment. Cancer Lett. 1996;104:7–12.CrossRef
42.
go back to reference Amant F, Moerman P, Neven P, Timmerman D, Van Limbergen E, Vergote I. Endometrial cancer. The Lancet. 2005;366:491–505.CrossRef Amant F, Moerman P, Neven P, Timmerman D, Van Limbergen E, Vergote I. Endometrial cancer. The Lancet. 2005;366:491–505.CrossRef
43.
go back to reference Wang F, Liu Y, Bi Z. Pioglitazone inhibits growth of human retinoblastoma cells via regulation of NF-κB inflammation signals. J Recept Signal Transduction. 2017;37:94–9.CrossRef Wang F, Liu Y, Bi Z. Pioglitazone inhibits growth of human retinoblastoma cells via regulation of NF-κB inflammation signals. J Recept Signal Transduction. 2017;37:94–9.CrossRef
44.
go back to reference Galli A, Mello T, Ceni E, Surrenti E, Surrenti C. The potential of antidiabetic thiazolidinediones for anticancer therapy. Expert Opin Investig Drugs. 2006;15:1039–49.CrossRef Galli A, Mello T, Ceni E, Surrenti E, Surrenti C. The potential of antidiabetic thiazolidinediones for anticancer therapy. Expert Opin Investig Drugs. 2006;15:1039–49.CrossRef
45.
go back to reference Ciaramella V, Sasso FC, Di Liello R, Corte CMD, Barra G, Viscardi G, et al. Activity and molecular targets of pioglitazone via blockade of proliferation, invasiveness and bioenergetics in human NSCLC. J Exp Clin Cancer Res. 2019;38:178.CrossRef Ciaramella V, Sasso FC, Di Liello R, Corte CMD, Barra G, Viscardi G, et al. Activity and molecular targets of pioglitazone via blockade of proliferation, invasiveness and bioenergetics in human NSCLC. J Exp Clin Cancer Res. 2019;38:178.CrossRef
Metadata
Title
Preliminary evaluation on the beneficial effects of pioglitazone in the treatment of endometrial cancer
Authors
Garikapati Kusuma Kumari
Ammu V. V. V. Ravi Kiran
Praveen T. Krishnamurthy
Publication date
01-06-2021
Publisher
Springer US
Published in
Medical Oncology / Issue 6/2021
Print ISSN: 1357-0560
Electronic ISSN: 1559-131X
DOI
https://doi.org/10.1007/s12032-021-01521-x

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