Generic placeholder image

Current Cancer Drug Targets

Editor-in-Chief

ISSN (Print): 1568-0096
ISSN (Online): 1873-5576

Research Article

VX-765 has a Protective Effect on Mice with Ovarian Injury Caused by Chemotherapy

Author(s): Pingyin Lee, Canquan Zhou and Xiaokun Hu*

Volume 23, Issue 4, 2023

Published on: 21 October, 2022

Page: [307 - 318] Pages: 12

DOI: 10.2174/1568009622666220930110024

open access plus

Abstract

Background: Malignant tumors continue to remain a main global public health issue. In the past 40 years, due to strides made in multi-disciplinary comprehensive treatment schemes for patients suffering from malignant tumors, especially chemotherapy schemes, the survival rate has been greatly improved in such patients. This group can be expected to maintain their fertility or have restored endocrine function following successful malignant tumor treatment. Therefore, focusing on the ovarian damage caused by chemotherapy in women of childbearing age is vital in order to protect their fertility and improve their quality of life.

Objective: This study attempted to evaluate whether VX-765 possesses an ovarian protective effect in ovarian injury induced by chemotherapy in the mice model.

Methods: Female C57BL/6J mice were administered with VX-765 gavage once a day for 21 consecutive days. Use of cyclophosphamide (Cy) began one week after the last gavage administration of VX- 765. Detailed classification of follicles at various levels was then quantified in each group. Immunohistochemistry and Western blot analysis were then used in order to analyze the expression of key proteins (FOXO3a, mTOR, RPS6 and AKT) as well as their phosphorylation of the PI3K / PTEN / AKT pathways in the ovary. The concentrations of AMH were measured by ELISA.

Results: The follicles at all levels of Cy treated mice were less than those of the normal group (P < 0.05). Meanwhile, mice treated with VX-765 prior to receiving Cy treatment had more primordial follicles (PMF) than mice treated with Cy alone (P < 0.05). In early growing follicles (EGF) and antral follicles (AF), no difference was observed among the experimental groups (P > 0.05), however, they were lower than those in the normal group (P < 0.05). In mice treated with continuous Cy, the total follicle number (TF) of mice combined with VX-765 (C-Cy-Vx765) was higher than that of mice without VX-765, and the TF of the two groups was lower than that of the normal group (P < 0.05). The value of PMF/TF in C-Cy-Vx765 group was significantly higher than that in the other three groups, while that of EGF/TF was significantly lower (P < 0.05). Immunohistochemical results showed that the phosphorylated forms of the main proteins of the PI3K / PTEN / AKT pathway were found to be more positive in Cy treated mice. The Western blot analysis showed that when Cy and VX-765 were cotreated, the increased levels of these phosphorylated proteins decreased compared with those treated with Cy alone. The AMH level of infancy Cy and VX-765 co-treated mice was higher than that of infancy normal mice (P < 0.05). After the mice grew to sexual maturity, the AMH level of Cy and VX- 765 co-treated mice was still higher than that of Cy treated mice (P < 0.05), and there was no significant difference with normal mice (P > 0.05).

Conclusion: VX-765 can maintain the level of AMH and inhibit the recruitment of PMF, thus protecting mice from Cy induced gonadotropic toxicity. Accordingly, VX-765 may play a protective role in mice with ovarian injury caused by chemotherapy.

Keywords: VX-765, cyclophosphamide, ovarian injury, ovarian protection, PI3K / PTEN / AKT pathway, burn out.

Graphical Abstract
[1]
Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer statistics, 2020. CA Cancer J. Clin., 2020, 70(1), 7-30.
[http://dx.doi.org/10.3322/caac.21590] [PMID: 31912902]
[2]
Coccia, P.F.; Pappo, A.S.; Beaupin, L.; Borges, V.F.; Borinstein, S.C.; Chugh, R.; Dinner, S.; Folbrecht, J.; Frazier, A.L.; Goldsby, R.; Gubin, A.; Hayashi, R.; Huang, M.S.; Link, M.P.; Livingston, J.A.; Matloub, Y.; Millard, F.; Oeffinger, K.C.; Puccetti, D.; Reed, D.; Robinson, S.; Rosenberg, A.R.; Sanft, T.; Spraker-Perlman, H.L.; von Mehren, M.; Wechsler, D.S.; Whelan, K.F.; Yeager, N.; Gurski, L.A.; Shead, D.A. Adolescent and young adult oncology, version 2.2018, NCCN clinical practice guidelines in Oncology. J. Natl. Compr. Canc. Netw., 2018, 16(1), 66-97.
[http://dx.doi.org/10.6004/jnccn.2018.0001] [PMID: 29295883]
[3]
Donnez, J.; Martinez-Madrid, B.; Jadoul, P.; Van Langendonckt, A.; Demylle, D.; Dolmans, M.M. Ovarian tissue cryopreservation and transplantation: A review. Hum. Reprod. Update, 2006, 12(5), 519-535.
[http://dx.doi.org/10.1093/humupd/dml032] [PMID: 16849817]
[4]
Morgan, S.; Anderson, R.A.; Gourley, C.; Wallace, W.H.; Spears, N. How do chemotherapeutic agents damage the ovary? Hum. Reprod. Update, 2012, 18(5), 525-535.
[http://dx.doi.org/10.1093/humupd/dms022] [PMID: 22647504]
[5]
Meirow, D. Reproduction post-chemotherapy in young cancer patients. Mol. Cell. Endocrinol., 2000, 169, 123-131.
[http://dx.doi.org/10.1016/S0303-7207(00)00365-8]
[6]
Levine, J.M.; Kelvin, J.F.; Quinn, G.P.; Gracia, C.R. Infertility in reproductive-age female cancer survivors. Cancer, 2015, 121(10), 1532-1539.
[http://dx.doi.org/10.1002/cncr.29181] [PMID: 25649243]
[7]
Bruning, P.F.; Pit, M.J.; de Jong-Bakker, M.; van den Ende, A.; Hart, A.; van Enk, A. Bone mineral density after adjuvant chemotherapy for premenopausal breast cancer. Br. J. Cancer, 1990, 61(2), 308-310.
[http://dx.doi.org/10.1038/bjc.1990.58] [PMID: 2310683]
[8]
Jeanes, H.; Newby, D.; Gray, G.A. Cardiovascular risk in women: The impact of hormone replacement therapy and prospects for new therapeutic approaches. Expert Opin. Pharmacother., 2007, 8(3), 279-288.
[http://dx.doi.org/10.1517/14656566.8.3.279] [PMID: 17266463]
[9]
Carter, J.; Rowland, K.; Chi, D.; Brown, C.; Abu-Rustum, N.; Castiel, M.; Barakat, R. Gynecologic cancer treatment and the impact of cancer-related infertility. Gynecol. Oncol., 2005, 97(1), 90-95.
[http://dx.doi.org/10.1016/j.ygyno.2004.12.019] [PMID: 15790443]
[10]
Medicine PCotASfR. Fertility preservation in patients undergoing gonadotoxic therapy or gonadectomy: A committee opinion. Fertil. Steril., 2019, 112(6), 1022-1033.
[http://dx.doi.org/10.1016/j.fertnstert.2019.09.013] [PMID: 31843073]
[11]
Blumenfeld, Z.; Eckman, A. Preservation of fertility and ovarian function and minimization of chemotherapy-induced gonadotoxicity in young women by GnRH-a. J. Natl. Cancer Inst. Monographs, 2005, 34, 40-43.
[http://dx.doi.org/10.1093/jncimonographs/lgi015]
[12]
Sonigo, C.; Beau, I.; Grynberg, M.; Binart, N. AMH prevents primordial ovarian follicle loss and fertility alteration in cyclophosphamide treated mice. FASEB J., 2019, 33(1), 1278-1287.
[http://dx.doi.org/10.1096/fj.201801089R] [PMID: 30113879]
[13]
Pariente, R.; Pariente, J.A.; Rodríguez, A.B.; Espino, J. Melatonin sensitizes human cervical cancer HeLa cells to cisplatin-induced cytotoxicity and apoptosis: Effects on oxidative stress and DNA fragmentation. J. Pineal Res., 2016, 60(1), 55-64.
[http://dx.doi.org/10.1111/jpi.12288] [PMID: 26462739]
[14]
Hsueh, A.; McGee, E.; Hayashi, M.; Hsu, S. Hormonal regulation of early follicle development in the rat ovary. Mol. Cell. Endocrinol., 2000, 163, 95-100.
[http://dx.doi.org/10.1016/S0303-7207(99)00245-2]
[15]
Li, Y.; Qiu, W.; Zhang, Z.; Han, X.; Bu, G.; Meng, F.; Kong, F.; Cao, X.; Huang, A.; Feng, Z.; Li, Y.; Zeng, X.; Du, X. Oral oyster polypeptides protect ovary against D -galactose-induced premature ovarian failure in C57BL/6 mice. J. Sci. Food Agric., 2020, 100(1), 92-101.
[http://dx.doi.org/10.1002/jsfa.9997] [PMID: 31435952]
[16]
Yan, Z.; Dai, Y.; Fu, H.; Zheng, Y.; Bao, D.; Yin, Y.; Chen, Q.; Nie, X.; Hao, Q.; Hou, D.; Cui, Y. Curcumin exerts a protective effect against premature ovarian failure in mice. J. Mol. Endocrinol., 2018, 60(3), 261-271.
[http://dx.doi.org/10.1530/JME-17-0214] [PMID: 29437881]
[17]
Teixeira, C.; Florencio-Silva, R.; Sasso, G.; Carbonel, A.; Simões, R.; Simões, M. Soy isoflavones protect against oxidative stress and diminish apoptosis in ovary of middle-aged female rats. Gynecol. Endocrinol., 2019, 35(7), 586-590.
[18]
Zhao, M.D.; Li, J.Q.; Chen, F.Y.; Dong, W.; Wen, L.J.; Fei, W.D.; Zhang, X.; Yang, P.L.; Zhang, X.M.; Zheng, C.H. Co-delivery of curcumin and paclitaxel by “core-shell” targeting amphiphilic copolymer to reverse resistance in the treatment of ovarian cancer. Int. J. Nanomedicine, 2019, 14(14), 9453-9467.
[http://dx.doi.org/10.2147/IJN.S224579] [PMID: 31819443]
[19]
Roness, H.; Gavish, Z.; Cohen, Y.; Meirow, D. Ovarian follicle burnout: A universal phenomenon? Cell Cycle, 2013, 12(20), 3245-3246.
[http://dx.doi.org/10.4161/cc.26358] [PMID: 24036538]
[20]
Meirow, D.; Biederman, H.; Anderson, R.A.; Wallace, W.H.B. Toxicity of chemotherapy and radiation on female reproduction. Clin. Obstet. Gynecol., 2010, 53(4), 727-739.
[http://dx.doi.org/10.1097/GRF.0b013e3181f96b54] [PMID: 21048440]
[21]
Kalich-Philosoph, L.; Roness, H.; Carmely, A.; Fishel-Bartal, M.; Ligumsky, H.; Paglin, S.; Wolf, I.; Kanety, H.; Sredni, B.; Meirow, D. Cyclophosphamide triggers follicle activation and “burnout”; AS101 prevents follicle loss and preserves fertility. Sci. Transl. Med., 2013, 5(185), 185ra62.
[http://dx.doi.org/10.1126/scitranslmed.3005402] [PMID: 23677591]
[22]
Wannamaker, W.; Davies, R.; Namchuk, M.; Pollard, J.; Ford, P.; Ku, G.; Decker, C.; Charifson, P.; Weber, P.; Germann, U.; Kuida, K.; Randle, J. (S)-1-((S)-2-{[1-(4-amino-3-chloro-phenyl)-methanoyl]-amino}-3,3-dimethyl-butanoyl)-pyrrolidine-2-carboxylic acid ((2R,3S)-2-ethoxy-5-oxo-tetrahydro-furan-3-yl)-amide (VX-765), an orally available selective interleukin (IL)-converting enzyme/caspase-1 inhibitor, exhibits potent anti-inflammatory activities by inhibiting the release of IL-1beta and IL-18. J. Pharmacol. Exp. Ther., 2007, 321(2), 509-516.
[http://dx.doi.org/10.1124/jpet.106.111344] [PMID: 17289835]
[23]
Pedersen, T.; Peters, H. Proposal for a classification of oocytes and follicles in the mouse ovary. Reproduction, 1968, 17(3), 555-557.
[http://dx.doi.org/10.1530/jrf.0.0170555] [PMID: 5715685]
[24]
Meirow, D.; Lewis, H.; Nugent, D.; Epstein, M. Subclinical depletion of primordial follicular reserve in mice treated with cyclophosphamide: Clinical importance and proposed accurate investigative tool. Hum. Reprod., 1999, 14(7), 1903-1907.
[http://dx.doi.org/10.1093/humrep/14.7.1903] [PMID: 10402415]
[25]
Donnez, J.; Dolmans, M.M.; Demylle, D.; Jadoul, P.; Pirard, C.; Squifflet, J.; Martinez-Madrid, B.; Van Langendonckt, A. Livebirth after orthotopic transplantation of cryopreserved ovarian tissue. Lancet, 2004, 364(9443), 1405-1410.
[http://dx.doi.org/10.1016/S0140-6736(04)17222-X] [PMID: 15488215]
[26]
Turner, N.H.; Partridge, A.; Sanna, G.; Di Leo, A.; Biganzoli, L. Utility of gonadotropin-releasing hormone agonists for fertility preservation in young breast cancer patients: The benefit remains uncertain. Ann. Oncol., 2013, 24(9), 2224-2235.
[http://dx.doi.org/10.1093/annonc/mdt196] [PMID: 23709175]
[27]
Morita, Y.; Perez, G.I.; Paris, F.; Miranda, S.R.; Ehleiter, D.; Haimovitz-Friedman, A.; Fuks, Z.; Xie, Z.; Reed, J.C.; Schuchman, E.H.; Kolesnick, R.N.; Tilly, J.L. Oocyte apoptosis is suppressed by disruption of the acid sphingomyelinase gene or by sphingosine -1-phosphate therapy. Nat. Med., 2000, 6(10), 1109-1114.
[http://dx.doi.org/10.1038/80442] [PMID: 11017141]
[28]
Kim, S-Y.; Cordeiro, M.H.; Serna, V.A.; Ebbert, K.; Butler, L.M.; Sinha, S.; Mills, A.A.; Woodruff, T.K.; Kurita, T. Rescue of platinum-damaged oocytes from programmed cell death through inactivation of the p53 family signaling network. Cell Death Differ., 2013, 20(8), 987-997.
[http://dx.doi.org/10.1038/cdd.2013.31] [PMID: 23598363]
[29]
Li, F.; Turan, V.; Lierman, S.; Cuvelier, C.; De Sutter, P.; Oktay, K. Sphingosine-1-phosphate prevents chemotherapy-induced human primordial follicle death. Hum. Reprod., 2014, 29(1), 107-113.
[http://dx.doi.org/10.1093/humrep/det391] [PMID: 24221908]
[30]
Skaznik-Wikiel, M.E.; McGuire, M.M.; Sukhwani, M.; Donohue, J.; Chu, T.; Krivak, T.C.; Rajkovic, A.; Orwig, K.E. Granulocyte colony-stimulating factor with or without stem cell factor extends time to premature ovarian insufficiency in female mice treated with alkylating chemotherapy. Fertil. Steril., 2013, 99(7), 2045-2054.e3.
[http://dx.doi.org/10.1016/j.fertnstert.2013.01.135] [PMID: 23453120]
[31]
Roness, H.; Kalich-Philosoph, L.; Meirow, D. Prevention of chemotherapy-induced ovarian damage: Possible roles for hormonal and non-hormonal attenuating agents. Hum. Reprod. Update, 2014, 20(5), 759-774.
[http://dx.doi.org/10.1093/humupd/dmu019] [PMID: 24833728]
[32]
Chang, E.M.; Lim, E.; Yoon, S.; Jeong, K.; Bae, S.; Lee, D.R.; Yoon, T.K.; Choi, Y.; Lee, W.S. Cisplatin induces overactivation of the dormant primordial follicle through PTEN/AKT/FOXO3a pathway which leads to loss of ovarian reserve in mice. PLoS One, 2015, 10(12), e0144245.
[http://dx.doi.org/10.1371/journal.pone.0144245] [PMID: 26656301]
[33]
Zhou, L.; Xie, Y.; Li, S.; Liang, Y.; Qiu, Q.; Lin, H.; Zhang, Q. Rapamycin prevents cyclophosphamide-induced over-activation of primordial follicle pool through PI3K/Akt/mTOR signaling pathway in vivo. J. Ovarian Res., 2017, 10(1), 56.
[http://dx.doi.org/10.1186/s13048-017-0350-3] [PMID: 28814333]
[34]
Chen, X.Y.; Xia, H.X.; Guan, H.Y.; Li, B.; Zhang, W. Follicle loss and apoptosis in cyclophosphamide-treated mice: What’s the matter? Int. J. Mol. Sci., 2016, 17(6), 836.
[http://dx.doi.org/10.3390/ijms17060836] [PMID: 27248997]
[35]
Ravizza, T.; Noé, F.; Zardoni, D.; Vaghi, V.; Sifringer, M.; Vezzani, A. Interleukin converting enzyme inhibition impairs kindling epileptogenesis in rats by blocking astrocytic IL-1β production. Neurobiol. Dis., 2008, 31(3), 327-333.
[http://dx.doi.org/10.1016/j.nbd.2008.05.007] [PMID: 18632279]
[36]
Reddy, P.; Zheng, W.; Liu, K. Mechanisms maintaining the dormancy and survival of mammalian primordial follicles. Trends Endocrinol. Metab., 2010, 21(2), 96-103.
[http://dx.doi.org/10.1016/j.tem.2009.10.001] [PMID: 19913438]
[37]
Adhikari, D.; Liu, K. Molecular mechanisms underlying the activation of mammalian primordial follicles. Endocr. Rev., 2009, 30(5), 438-464.
[http://dx.doi.org/10.1210/er.2008-0048] [PMID: 19589950]
[38]
van Rooij, I.; Tonkelaar, I.; Broekmans, F.; Looman, C.; Scheffer, G.; de Jong, F.; Themmen, A.; te Velde, E. Anti-müllerian hormone is a promising predictor for the occurrence of the menopausal transition. Menopause, 2004, 11, 601-606.
[http://dx.doi.org/10.1097/01.GME.0000123642.76105.6E]
[39]
Bala, J.; Seth, S.; Dhankhar, R.; Ghalaut, V.S. Chemotherapy: Impact on anti- müllerian hormone levels in breast carcinoma. J. Clin. Diagn. Res., 2016, 10(2), BC19-BC21.
[http://dx.doi.org/10.7860/JCDR/2016/15933.7328] [PMID: 27042447]
[40]
Peigné, M.; Decanter, C. Serum AMH level as a marker of acute and long-term effects of chemotherapy on the ovarian follicular content: A systematic review. Reprod. Biol. Endocrinol., 2014, 12, 26.
[41]
Henry, N.L.; Xia, R.; Schott, A.F.; McConnell, D.; Banerjee, M.; Hayes, D.F. Prediction of postchemotherapy ovarian function using markers of ovarian reserve. Oncologist, 2014, 19(1), 68-74.
[http://dx.doi.org/10.1634/theoncologist.2013-0145] [PMID: 24319018]
[42]
Donnez, J.; Dolmans, M.M. Fertility preservation in women. N. Engl. J. Med., 2017, 377(17), 1657-1665.
[http://dx.doi.org/10.1056/NEJMra1614676] [PMID: 29069558]
[43]
Spears, N.; Lopes, F.; Stefansdottir, A.; Rossi, V.; De Felici, M.; Anderson, R.A.; Klinger, F.G. Ovarian damage from chemotherapy and current approaches to its protection. Hum. Reprod. Update, 2019, 25(6), 673-693.
[http://dx.doi.org/10.1093/humupd/dmz027] [PMID: 31600388]
[44]
Goldman, K.N.; Chenette, D.; Arju, R.; Duncan, F.E.; Keefe, D.L.; Grifo, J.A.; Schneider, R.J. mTORC1/2 inhibition preserves ovarian function and fertility during genotoxic chemotherapy. Proc. Natl. Acad. Sci. USA, 2017, 114(12), 3186-3191.
[http://dx.doi.org/10.1073/pnas.1617233114] [PMID: 28270607]
[45]
Jang, H.; Na, Y.; Hong, K.; Lee, S.; Moon, S.; Cho, M.; Park, M.; Lee, O.H.; Chang, E.M.; Lee, D.R.; Ko, J.J.; Lee, W.S.; Choi, Y. Synergistic effect of melatonin and ghrelin in preventing cisplatin-induced ovarian damage via regulation of FOXO3a phosphorylation and binding to the p27Kip1 promoter in primordial follicles. J. Pineal Res., 2017, 63(3), e12432.
[http://dx.doi.org/10.1111/jpi.12432] [PMID: 28658519]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy