Skip to main content
SpringerLink
Log in

Melatonin Reverses 10-Hydroxycamptothecin-Induced Apoptosis and Autophagy in Mouse Oocyte

  • Reproductive Biology: Original Article
  • Published:
Reproductive Sciences Aims and scope Submit manuscript

Abstract

10-Hydroxycamptothecin (HCPT) is a widely used anticancer drug that induces cytotoxicity by triggering the cell apoptotic pathway. Studies have shown that HCPT has harmful effects on normal cells, but whether HCPT affects the development of mouse oocytes in vitro has not been reported. First, this study investigated the development of oocytes exposed to 60 μM HCPT in vitro. In the HCPT-treated group, the first polar body extrusion (PBE) rate of oocytes decreased, spindle morphology was abnormal, DNA double-strand break, oxidative stress level increased, and mitochondrial distribution was abnormal. The apoptosis and autophagy levels of oocytes in the HCPT-treated group were detected by qRT-PCR and western blot. Compared with the control group, the expressions of key regulators of oocyte apoptosis (bax, caspase-3) and autophagy (lc3, beclin, ATG12) pathway were increased in the HCPT-treated group. HCPT treatment induced apoptosis and autophagy in oocytes. Melatonin (MT) can protect cell structure, prevent DNA damage, and reduce the content of peroxides. So we wondered whether MT could ameliorate the harmful effects of mouse oocytes induced by HCPT. Interestingly, the addition of 1 mM MT can protect oocytes from HCPT toxicity to some extent. Compared with the HCPT group, the addition of 1 mM MT increased the PBE ratio of oocytes, decreased ROS levels, and decreased spindle abnormalities and DNA breakage ratio. In summary, these results revealed that HCPT exhibited adverse effects on mouse oocyte maturation and quality, and MT administration alleviated the negative influence of HCPT.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Data Availability

Available.

References

  1. Morgan S, Anderson RA, Gourley C, Wallace WH, Spears N. How do chemotherapeutic agents damage the ovary? Hum Reprod Update. 2012;18(5):525–35. https://doi.org/10.1093/humupd/dms022.

    Article  CAS  PubMed  Google Scholar 

  2. Anderson RA, Mitchell RT, Kelsey TW, Spears N, Telfer EE, Wallace WHB. Cancer treatment and gonadal function: experimental and established strategies for fertility preservation in children and young adults. Lancet Diabetes Endocrinol. 2015;3(7):556–67.

    Article  CAS  Google Scholar 

  3. Salama M, Woodruff TK. Anticancer treatments and female fertility: clinical concerns and role of oncologists in oncofertility practice. Expert Rev Anticancer Ther. 2017;17(8):687–92.

  4. Xiao S, Zhang J, Liu M, Iwahata H, Rogers HB, Woodruff TK. Doxorubicin has dose-dependent toxicity on mouse ovarian follicle development, hormone secretion, and oocyte maturation. Toxicological sciences : an official journal of the Society of Toxicology. 2017;157(2):320–9.

  5. Fu YR, Yi ZJ, Yan YR, Qiu ZY. Hydroxycamptothecin-induced apoptosis in hepatoma SMMC-7721 cells and the role of mitochondrial pathway. Mitochondrion. 2006;6(4):211–7.

    Article  CAS  Google Scholar 

  6. Li X, Chen H, Sun Y, Dai J, Wang S, Wang J, et al. Hydroxycamptothecin prevents intraarticular scar adhesion by activating the PERK signal pathway. Eur J Pharmacol. 2017;810:36–43.

    Article  CAS  Google Scholar 

  7. Gen Z, Lei D, Randall R, Xuemei W, Qun L, Shouquan H, et al. Hydroxycamptothecin-loaded Fe3O4 nanoparticles induce human lung cancer cell apoptosis through caspase-8 pathway activation and disrupt tight junctions. Cancer Sci. 2011;102(6):1216–22.

    Article  Google Scholar 

  8. Wang A, Li S. Hydroxycamptothecin-loaded nanoparticles enhance target drug delivery and anticancer effect. BMC Biotechnol. 2008;8(1):46.

    Article  Google Scholar 

  9. Yueh-Hsin P, Hsin-Chen L, Jen-Yi L, Pin-Ho W, Li-Kang H, Chin-Wen C, et al. Anticancer effects of low-dose 10-hydroxycamptothecin in human colon cancer. Oncol Rep. 2006;15(5):1273–9.

    Google Scholar 

  10. Wei W, San-Jun S, Jie L, Xun S, Ke R, Dong Z, et al. Lipid nanoparticles loaded with 10-hydroxycamptothecin-phospholipid complex developed for the treatment of hepatoma in clinical application. J Drug Target. 2010;18(7):557–66.

    Article  CAS  Google Scholar 

  11. Li YF, Zhang R. Reversed-phase high-performance liquid chromatography method for the simultaneous quantitation of the lactone and carboxylate forms of the novel natural product anticancer agent 10-hydroxycamptothecin in biological fluids and tissues. J Chromatogr B Biomed Sci Appl. 1996;686(2):257–65.

    Article  CAS  Google Scholar 

  12. Qin P, Wang J, Li J. The effect of 10-HCPT instillation pleural or abdominal cavity in the management of malignant pleural effusion or ascites. Chinese J Cancer Prev Treat. 1999;(01):3–5.

  13. Wang H, Feng J, Liu G, Chen B, Jiang Y, Xie Q. In vitro and in vivo anti-tumor efficacy of 10-hydroxycamptothecin polymorphic nanoparticle dispersions: shape- and polymorph-dependent cytotoxicity and delivery of 10-hydroxycamptothecin to cancer cells. Nanomedecine. 2016;12(4):881–91. https://doi.org/10.1016/j.nano.2015.12.373.

    Article  CAS  Google Scholar 

  14. Atashrazm F, Lowenthal RM, Woods GM, Holloway AF, Dickinson JL. Fucoidan and cancer: a multifunctional molecule with anti-tumor potential. Mar Drugs. 2015;13(4):2327–46.

    Article  CAS  Google Scholar 

  15. Won Duk J, Irene V, Gil M. Targeted cancer therapy - are the days of systemic chemotherapy numbered? Maturitas. 2013;76(4):308–14.

    Article  Google Scholar 

  16. Zhao H, Wu M, Zhu L, Tian Y, Wu M, Li Y, et al. Cell-penetrating peptide-modified targeted drug-loaded phase-transformation lipid nanoparticles combined with low-intensity focused ultrasound for precision theranostics against hepatocellular carcinoma. Theranostics. 2018;8(7):1892–910. https://doi.org/10.7150/thno.22386.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Overbeek A, Mh VDB, van Leeuwen FE, Kaspers GJ, Lambalk CB, van Dulmen-den Broder E. Chemotherapy-related late adverse effects on ovarian function in female survivors of childhood and young adult cancer: a systematic review. Cancer Treat Rev. 2016;53:10.

    Article  Google Scholar 

  18. James SE, Burden H, Burgess R, Xie Y, Tao Y, Massa SM, et al. Anti-cancer drug induced neurotoxicity and identification of Rho pathway signaling modulators as potential neuroprotectants. Neurotoxicology. 2008;29(4):605–12.

    Article  CAS  Google Scholar 

  19. Miao Y, Zhou C, Bai Q, Cui Z, Shiyang X, Lu Y, et al. The protective role of melatonin in porcine oocyte meiotic failure caused by the exposure to benzo(a)pyrene. Hum Reprod. 2017;33(1):1.

    Google Scholar 

  20. Park HJ, Park JY, Kim JW, Yang SG, Jung JM, Kim MJ, et al. Melatonin improves the meiotic maturation of porcine oocytes by reducing endoplasmic reticulum stress during in vitro maturation. J Pineal Res. 2018;64(2):e12458.

    Article  Google Scholar 

  21. Tamura H, Kawamoto M, Sato S, Tamura I, Maekawa R, Taketani T, et al. Long term melatonin treatment delays ovarian aging. J Pineal Res. 2017;62(2). https://doi.org/10.1111/jpi.12381.

  22. Gloria BK. Melatonin as a cytoskeletal modulator: implications for cell physiology and disease. J Pineal Res. 2010;40(1):1–9.

    Google Scholar 

  23. Zhang M, Dai X, Lu Y, Miao Y, Zhou C, Cui Z, et al. Melatonin protects oocyte quality from bisphenol A-induced deterioration in the mouse. J Pineal Res. 2017;62(3). https://doi.org/10.1111/jpi.12396.

  24. Reiter RJ. Melatonin and human reproduction. Ann Med. 1998;30(1):103–8.

    Article  CAS  Google Scholar 

  25. Pang YW, Sun YQ, Sun WJ, Du WH, Hao HS, Zhao SJ, et al. Melatonin inhibits paraquat-induced cell death in bovine preimplantation embryos. J Pineal Res. 2016;60(2):155–66.

    Article  CAS  Google Scholar 

  26. Hong-Mei Z, Yiqiang Z. Melatonin: a well-documented antioxidant with conditional pro-oxidant actions. J Pineal Res. 2015;57(2):131–46.

    Google Scholar 

  27. Lan M, Han J, Pan MH, Wan X, Pan ZN, Sun SC. Melatonin protects against defects induced by deoxynivalenol during mouse oocyte maturation. J Pineal Res. 2018;65(1):e12477. https://doi.org/10.1111/jpi.12477.

  28. Li FP, Zhou JL, Guo AW, Liu Y, Zhang F, Xu BH, et al. Di(n-butyl) phthalate exposure impairs meiotic competence and development of mouse oocyte. Environ Pollut. 2019;246:597–607. https://doi.org/10.1016/j.envpol.2018.12.077.

    Article  CAS  PubMed  Google Scholar 

  29. Wei Y, Li C, Zhang Y, He H, Zhang G, Hao X, et al. Hydroxycamptothecin mediates antiproliferative effects through apoptosis and autophagy in A549 cells. Oncol Lett. 2018;15(5):6322–8. https://doi.org/10.3892/ol.2018.8107.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Pan C, Hu YF, Yi HS, Song J, Wang L, Pan MH, et al. Role of Bmbuffy in hydroxycamptothecine-induced apoptosis in BmN-SWU1 cells of the silkworm, Bombyx mori. Biochem Biophys Res Commun. 2014;447(2):237–43. https://doi.org/10.1016/j.bbrc.2014.03.093.

    Article  CAS  PubMed  Google Scholar 

  31. Zhang L, Zhang Z, Wang J, Lv D, Zhu T, Wang F, et al. Melatonin regulates the activities of ovary and delays the fertility decline in female animals via MT1/AMPK pathway. J Pineal Res. 2019;66(3):e12550. https://doi.org/10.1111/jpi.12550.

    Article  CAS  PubMed  Google Scholar 

  32. Dai X, Lu Y, Zhang M, Miao Y, Zhou C, Cui Z, et al. Melatonin improves the fertilization ability of post-ovulatory aged mouse oocytes by stabilizing ovastacin and Juno to promote sperm binding and fusion. Hum Reprod. 2017;32(3):598–606. https://doi.org/10.1093/humrep/dew362.

    Article  CAS  PubMed  Google Scholar 

  33. Sun ZY, Zhang P, Wang JJ, Liu JC, Li L, Shen W, et al. Melatonin alleviates meiotic defects in fetal mouse oocytes induced by Di (2-ethylhexyl) phthalate in vitro. Aging. 2018;10(12):4175–87. https://doi.org/10.18632/aging.101715.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Li WD, Yu S, Luo SM, Shen W, Yin S. Melatonin defends mouse oocyte quality from benzo[ghi]perylene-induced deterioration. J Cell Physiol. 2019;234(5):6220–9. https://doi.org/10.1002/jcp.27351.

    Article  CAS  PubMed  Google Scholar 

  35. Marnett LJ. Oxyradicals and DNA damage. Carcinogenesis. 2000;21(3):361–70. https://doi.org/10.1093/carcin/21.3.361.

    Article  CAS  PubMed  Google Scholar 

  36. Pfeiffer P, Goedecke W, Obe G. Mechanisms of DNA double-strand break repair and their potential to induce chromosomal aberrations. Mutagenesis. 2000;15(4):289–302. https://doi.org/10.1093/mutage/15.4.289.

    Article  CAS  PubMed  Google Scholar 

  37. Staurengo-Ferrari L, Badaro-Garcia S, Hohmann MSN, Manchope MF, Zaninelli TH, Casagrande R, et al. Contribution of Nrf2 modulation to the mechanism of action of analgesic and anti-inflammatory drugs in pre-clinical and clinical stages. Front Pharmacol. 2018;9:1536. https://doi.org/10.3389/fphar.2018.01536.

    Article  CAS  PubMed  Google Scholar 

  38. Li Y, Zhang Z, He C, Zhu K, Xu Z, Ma T, et al. Melatonin protects porcine oocyte in vitro maturation from heat stress. J Pineal Res. 2015;59(3):365–75.

    Article  CAS  Google Scholar 

  39. Rubio C, Simón C, Vidal F, Rodrigo L, Pehlivan T, Remohí J, et al. Chromosomal abnormalities and embryo development in recurrent miscarriage couples. Hum Reprod. 2003;18(1):182–8. https://doi.org/10.1093/humrep/deg015.

    Article  CAS  PubMed  Google Scholar 

  40. Xia L, Hou S, Ren X, Wang Z. Effects of thioglycolic acid on in vivo oocytes maturation in mice. PLoS One. 2011;6(9):e23996. https://doi.org/10.1371/journal.pone.0023996.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Zhu CC, Zhang Y, Duan X, Han J, Sun SC. Toxic effects of HT-2 toxin on mouse oocytes and its possible mechanisms. Arch Toxicol. 2016;90(6):1495–505.

    Article  CAS  Google Scholar 

  42. Duan X, Wang QC, Chen KL, Zhu CC, Liu J, Sun SC. Acrylamide toxic effects on mouse oocyte quality and fertility in vivo. Sci Rep. 2015;5:11562.

    Article  CAS  Google Scholar 

  43. Hou YJ, Xiong B, Zheng WJ, Duan X, Cui XS, Kim NH, et al. Oocyte quality in mice is affected by a mycotoxin-contaminated diet. Environ Mol Mutagen. 2014;55(4):354–62.

    Article  CAS  Google Scholar 

  44. Liu Y, He XQ, Huang X, Ding L, Xu L, Shen YT, et al. Resveratrol protects mouse oocytes from methylglyoxal-induced oxidative damage. PLoS One. 2013;8(10):e77960.

    Article  CAS  Google Scholar 

  45. Brevini TAL, Rita V, Chiara F, Fulvio G. Role of adenosine triphosphate, active mitochondria, and microtubules in the acquisition of developmental competence of parthenogenetically activated pig oocytes. Biol Reprod. 2005;72(5):1218–23.

    Article  CAS  Google Scholar 

  46. Tamura H, Takasaki A, Miwa I, Taniguchi K, Maekawa R, Asada H, et al. Oxidative stress impairs oocyte quality and melatonin protects oocytes from free radical damage and improves fertilization rate. J Pineal Res. 2010;44(3):280–7.

    Article  Google Scholar 

  47. Ren X, Zhang L, Zhang Y, Mao L, Jiang H. Oxidative stress induced by camptothecin and hydroxyl-camptothecin in IOZCAS-Spex-II cells of Spodoptera exigua Hübner. Comp Biochem Physiol C Toxicol Pharmacol. 2019;216:52–9. https://doi.org/10.1016/j.cbpc.2018.11.002.

    Article  CAS  PubMed  Google Scholar 

  48. Santoro R, Marani M, Blandino G, Muti P, Strano S. Melatonin triggers p53Ser phosphorylation and prevents DNA damage accumulation. Oncogene. 2011;31(24):2931–42.

    Article  Google Scholar 

  49. Fei B, Chi AL, Weng Y. Hydroxycamptothecin induces apoptosis and inhibits tumor growth in colon cancer by the downregulation of survivin and XIAP expression. World J Surg Oncol. 2013;11(1):120.

    Article  Google Scholar 

  50. Estaquier J, Vallette F, Vayssiere JL, Mignotte B. The mitochondrial pathways of apoptosis. Adv Exp Med Biol. 2012;942:157–83. https://doi.org/10.1007/978-94-007-2869-1_7.

    Article  CAS  PubMed  Google Scholar 

  51. Liao AJ, Hu R, Li YC, Yao K, Wang HH, Zhang R, et al. The study of FTY720 on inducing apoptosis and autophagy in multiple myeloma cell line U266. Zhonghua Xue Ye Xue Za Zhi. 2011;32(10):664–7.

    CAS  PubMed  Google Scholar 

  52. Parzych KR, Klionsky DJ. An overview of autophagy: morphology, mechanism, and regulation. Antioxid Redox Signal. 2014;20(3):460–73. https://doi.org/10.1089/ars.2013.5371.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This work was supported by the Special Fund for Basic Research on Scientific Instruments of the Chinese National Natural Science Foundation (grant no: 61633012, U1613220).

Author information

Author notes

  1. Lining Wang and Jingwen Zhang contributed equally to this work.

Authors and Affiliations

  1. College of Life Science, The Key Laboratory of Bioactive Materials, Ministry of Education, State Key Laboratory of Medicinal Chemical Biology, Nankai University, Weijin Road 94, Tianjin, 300071, China

    Lining Wang, Jingwen Zhang, Zhenzhen Jia & Xizeng Feng

  2. School of Biology and Biological Engineering, South China University of Technology, Guangzhou, 510006, China

    Chengtian Zhao

Authors
  1. Lining Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jingwen Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chengtian Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zhenzhen Jia
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xizeng Feng
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Xizeng Feng and Lining Wang conceived and designed the experiments. Lining Wang and Zhenzhen Jia made an important contribution to data analysis. Jingwen Zhang and Chengtian Zhao conducted the experiments and gene expression analysis. Lining Wang and Jingwen Zhang wrote the manuscript. All authors discussed the results and implications and reviewed the manuscript at all stages.

Corresponding author

Correspondence to Xizeng Feng.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Ethics Approval

All experiments involved animals were approved by the Animal Ethics Committee of Nankai University (No. 2008).

Consent to Participate

Not applicable.

Consent for Publication

Not applicable.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

ESM 1

(DOCX 21 kb).

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, L., Zhang, J., Zhao, C. et al. Melatonin Reverses 10-Hydroxycamptothecin-Induced Apoptosis and Autophagy in Mouse Oocyte. Reprod. Sci. 28, 1839–1849 (2021). https://doi.org/10.1007/s43032-020-00359-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s43032-020-00359-4

Keywords

Search

Navigation