Chemotherapy induced oxidative stress in the ovary: drug-dependent mechanisms and potential interventions

Abstract Cancer incidence and relative survival are expected to increase over the next few decades. With the majority of patients receiving combinatorial chemotherapy, an increasing proportion of patients experience long-term side effects from treatment—including reproductive disorders and infertility. A limited number of studies have examined mechanisms of single-agent chemotherapy-induced gonadotoxicity, with chemotherapy-induced oxidative stress being implicated in the loss of reproductive functions. Current methods of female fertility preservation are costly, invasive, only moderately successful, and seldom presented to cancer patients. The potential of antioxidants to alleviate chemotherapy has been overlooked at a time when it is becoming increasingly important to develop strategies to protect reproductive functions during chemotherapy. This review will summarize the importance of reactive oxygen species homeostasis in reproduction, chemotherapy-induced mitochondrial dysfunction in oocytes, chemotherapy-induced oxidative stress, and several promising natural adjuvants. Summary Sentence Chemotherapy-induced oxidative stress has long-lasting and devastating impacts on female fertility and reproduction; while there is a devastating lack of affordable and effective interventions available, antioxidants are potential adjuvants. Graphical Abstract

[1]  S. Sciarretta,et al.  Mitochondria and Doxorubicin-Induced Cardiomyopathy: A Complex Interplay , 2022, Cells.

[2]  R. S. Barberino,et al.  Protective Effects of Antioxidants on Cyclophosphamide-Induced Ovarian Toxicity. , 2022, Biopreservation and biobanking.

[3]  N. Suzuki,et al.  Paclitaxel is evidence to reduce growing ovarian follicle growth in mice model study. , 2022, Toxicology in vitro : an international journal published in association with BIBRA.

[4]  H. O’Neill,et al.  Genetic associations with polycystic ovary syndrome: the role of the mitochondrial genome; a systematic review and meta-analysis , 2022, Journal of Clinical Pathology.

[5]  A. Jemal,et al.  Cancer statistics, 2022 , 2022, CA: a cancer journal for clinicians.

[6]  D. Woods,et al.  Role of Granulosa Cells in the Aging Ovarian Landscape: A Focus on Mitochondrial and Metabolic Function , 2022, Frontiers in Physiology.

[7]  S-F Zheng,et al.  Effects of quercetin on ovarian function and regulation of the ovarian PI3K/Akt/FoxO3a signalling pathway and oxidative stress in a rat model of cyclophosphamide‐induced premature ovarian failure , 2021, Basic & clinical pharmacology & toxicology.

[8]  Fenge Li,et al.  Oxidative stress in oocyte aging and female reproduction , 2021, Journal of cellular physiology.

[9]  Songying Zhang,et al.  Cyclophosphamide Exposure Causes Long-Term Detrimental Effect of Oocytes Developmental Competence Through Affecting the Epigenetic Modification and Maternal Factors’ Transcription During Oocyte Growth , 2021, Frontiers in Cell and Developmental Biology.

[10]  Karla J. Hutt,et al.  Evaluation of mitochondria in mouse oocytes following cisplatin exposure , 2021, Journal of Ovarian Research.

[11]  V. Apostolopoulos,et al.  Mechanisms of Cisplatin-Induced Acute Kidney Injury: Pathological Mechanisms, Pharmacological Interventions, and Genetic Mitigations , 2021, Cancers.

[12]  Bo Yang,et al.  Natural products: potential treatments for cisplatin-induced nephrotoxicity , 2021, Acta Pharmacologica Sinica.

[13]  Jiaqiang Xiong,et al.  Therapy of Endocrine Disease: Novel protection and treatment strategies for chemotherapy-associated ovarian damage. , 2021, European journal of endocrinology.

[14]  Y. Kuang,et al.  Quercetin prevents primordial follicle loss via suppression of PI3K/Akt/Foxo3a pathway activation in cyclophosphamide-treated mice , 2020, Reproductive Biology and Endocrinology.

[15]  Carmen L. Wilson,et al.  Cohort Profile: The St. Jude Lifetime Cohort Study (SJLIFE) for paediatric cancer survivors. , 2020, International journal of epidemiology.

[16]  O. Bahri,et al.  Evaluation of ovarian reserve before and after chemotherapy. , 2020, Journal of gynecology obstetrics and human reproduction.

[17]  H. Abrahamse,et al.  Redox Potential of Antioxidants in Cancer Progression and Prevention , 2020, Antioxidants.

[18]  Jenifer R Prosperi,et al.  Mechanisms of Taxane Resistance , 2020, Cancers.

[19]  J. Abe,et al.  Mitochondria and chronic effects of cancer therapeutics: The clinical implications , 2020, Journal of Thrombosis and Thrombolysis.

[20]  N. Webster,et al.  Mitochondrial-dysfunction in obesity and reproduction. , 2020, Endocrinology.

[21]  J. Bhardwaj,et al.  Ameliorating Effects of Natural Antioxidant Compounds on Female Infertility: a Review , 2020, Reproductive Sciences.

[22]  G. Bedoschi,et al.  Impact of adjuvant chemotherapy or tamoxifen-alone on the ovarian reserve of young women with breast cancer , 2020, Breast Cancer Research and Treatment.

[23]  Yi Luan,et al.  Continuous treatment with cisplatin induces the oocyte death of primordial follicles without activation , 2020, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[24]  Kezhen Li,et al.  Transient impact of paclitaxel on mouse fertility and protective effect of gonadotropin-releasing hormone agonist , 2020, Oncology reports.

[25]  K. Oktay,et al.  Unraveling the mechanisms of chemotherapy-induced damage to human primordial follicle reserve: road to developing therapeutics for fertility preservation and reversing ovarian aging. , 2020, Molecular human reproduction.

[26]  Qian Deng,et al.  Therapeutic Potential of Quercetin as an Antiatherosclerotic Agent in Atherosclerotic Cardiovascular Disease: A Review , 2020, Evidence-based complementary and alternative medicine : eCAM.

[27]  U. Markert,et al.  Doxorubicin induces cytotoxicity and miR-132 expression in granulosa cells. , 2020, Reproductive toxicology.

[28]  P. Oliveira,et al.  Mitochondrial Determinants of Doxorubicin-Induced Cardiomyopathy. , 2020, Circulation research.

[29]  Gheyath K Nasrallah,et al.  Potential Adverse Effects of Resveratrol: A Literature Review , 2020, International journal of molecular sciences.

[30]  Weihua Huang,et al.  Electrochemical Monitoring of Paclitaxel-Induced ROS Release from Mitochondria inside Single Cells. , 2019, Small.

[31]  M. De Felici,et al.  Ovarian damage from chemotherapy and current approaches to its protection , 2019, Human reproduction update.

[32]  Lianwen Zheng,et al.  Polycystic ovary syndrome and mitochondrial dysfunction , 2019, Reproductive Biology and Endocrinology.

[33]  S. Ait-Oudhia,et al.  Insights into Doxorubicin-induced Cardiotoxicity: Molecular Mechanisms, Preventive Strategies, and Early Monitoring , 2019, Molecular Pharmacology.

[34]  Khoa N. Nguyen,et al.  Recent Advances in Models, Mechanisms, Biomarkers, and Interventions in Cisplatin-Induced Acute Kidney Injury , 2019, International journal of molecular sciences.

[35]  J. Ferlay,et al.  Estimates of global chemotherapy demands and corresponding physician workforce requirements for 2018 and 2040: a population-based study. , 2019, The Lancet. Oncology.

[36]  Shuai Jiang,et al.  Mitochondrial electron transport chain, ROS generation and uncoupling (Review) , 2019, International journal of molecular medicine.

[37]  Yuan-Lu Cui,et al.  Antioxidant activities of quercetin and its complexes 2 for medicinal application 3 , 2019 .

[38]  Meng Wu,et al.  Resveratrol alleviates chemotherapy-induced oogonial stem cell apoptosis and ovarian aging in mice , 2019, Aging.

[39]  T. Woodruff,et al.  Inhibitors of apoptosis protect the ovarian reserve from cyclophosphamide. , 2019, The Journal of endocrinology.

[40]  Sumit Sharma,et al.  Molecular mechanism involved in cyclophosphamide‐induced cardiotoxicity: Old drug with a new vision , 2019, Life sciences.

[41]  H. Sampath,et al.  Mitochondrial DNA Integrity: Role in Health and Disease , 2019, Cells.

[42]  K. Qin,et al.  Doxorubicin Induces ER Calcium Release via Src in Rat Ovarian Follicles , 2018, Toxicological sciences : an official journal of the Society of Toxicology.

[43]  T. L. Kek,et al.  Metabolomic profiling of serum in aging mice supplemented with tocotrienol-rich fraction for identification of female reproductive aging biomarkers , 2018, Malaysian Journal of Fundamental and Applied Sciences.

[44]  M. Al-Omran,et al.  Role of Endothelium in Doxorubicin-Induced Cardiomyopathy , 2018, JACC. Basic to translational science.

[45]  A. Hacışevki,et al.  An Overview of Melatonin as an Antioxidant Molecule: A Biochemical Approach , 2018, Melatonin - Molecular Biology, Clinical and Pharmaceutical Approaches.

[46]  R. Goldenberg,et al.  Doxorubicin-Induced Cardiotoxicity: From Mechanisms to Development of Efficient Therapy , 2018, Cardiotoxicity.

[47]  K. Książek,et al.  Comprehensive review on how platinum- and taxane-based chemotherapy of ovarian cancer affects biology of normal cells , 2018, Cellular and Molecular Life Sciences.

[48]  H. Kohan-Ghadr,et al.  Acrolein, a commonly found environmental toxin, causes oocyte mitochondrial dysfunction and negatively affects embryo development , 2018, Free radical research.

[49]  A. Mishra,et al.  Resveratrol: A Double-Edged Sword in Health Benefits , 2018, Biomedicines.

[50]  Yaoxing Chen,et al.  A novel and compact review on the role of oxidative stress in female reproduction , 2018, Reproductive Biology and Endocrinology.

[51]  Nikos Koundouros,et al.  Phosphoinositide 3-Kinase/Akt Signaling and Redox Metabolism in Cancer , 2018, Front. Oncol..

[52]  M. Bhori,et al.  Antioxidants as precision weapons in war against cancer chemotherapy induced toxicity – Exploring the armoury of obscurity , 2017, Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society.

[53]  Bhupinder Singh,et al.  Administration of antioxidants in cancer: debate of the decade. , 2018, Drug discovery today.

[54]  H. Kohan-Ghadr,et al.  Cyclophosphamide and acrolein induced oxidative stress leading to deterioration of metaphase II mouse oocyte quality , 2017, Free radical biology & medicine.

[55]  M. Çaydere,et al.  Dose dependent effect of resveratrol in preventing cisplatin-induced ovarian damage in rats: An experimental study. , 2017, Reproductive biology.

[56]  M. Brand,et al.  Production of superoxide and hydrogen peroxide from specific mitochondrial sites under different bioenergetic conditions , 2017, The Journal of Biological Chemistry.

[57]  T. Najafi Chemotherapy-Induced Oxidative Stress and Infertility , 2017 .

[58]  Xinyang Zhang,et al.  Enhanced Cisplatin Chemotherapy by Iron Oxide Nanocarrier-Mediated Generation of Highly Toxic Reactive Oxygen Species. , 2017, Nano letters.

[59]  Carmen L. Wilson,et al.  Approach for Classification and Severity Grading of Long-term and Late-Onset Health Events among Childhood Cancer Survivors in the St. Jude Lifetime Cohort , 2016, Cancer Epidemiology, Biomarkers & Prevention.

[60]  M. Brand Mitochondrial generation of superoxide and hydrogen peroxide as the source of mitochondrial redox signaling. , 2016, Free radical biology & medicine.

[61]  Wang-ming Xu,et al.  Oxidative Stress: Placenta Function and Dysfunction , 2016, American journal of reproductive immunology.

[62]  R. Reiter,et al.  Melatonin as an antioxidant: under promises but over delivers , 2016, Journal of pineal research.

[63]  Subramani Parasuraman,et al.  Overviews of Biological Importance of Quercetin: A Bioactive Flavonoid , 2016, Pharmacognosy reviews.

[64]  M. Christianson,et al.  Fertility Preservation: A Key Survivorship Issue for Young Women with Cancer , 2016, Front. Oncol..

[65]  A. Qureshi,et al.  Evaluation of Pharmacokinetics, and Bioavailability of Higher Doses of Tocotrienols in Healthy Fed Humans , 2016, Journal of clinical & experimental cardiology.

[66]  J. Rosenberg,et al.  Pharmacokinetics of oral and intravenous melatonin in healthy volunteers , 2016, BMC Pharmacology and Toxicology.

[67]  Changwei Wang,et al.  Taxane anticancer agents: a patent perspective , 2016, Expert opinion on therapeutic patents.

[68]  S. Temin,et al.  Systemic Therapy for Stage IV Non-Small-Cell Lung Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update. , 2016, Journal of oncology practice / American Society of Clinical Oncology.

[69]  F. Ciani,et al.  Influence of ROS on Ovarian Functions , 2015 .

[70]  Ferda Özkan,et al.  Protective effect of resveratrol against oxidative damage to ovarian reserve in female Sprague-Dawley rats. , 2015, Reproductive biomedicine online.

[71]  O. Krizanova,et al.  Calcium and ROS: A mutual interplay , 2015, Redox biology.

[72]  G. Froemming,et al.  Tocotrienol preserves ovarian function in cyclophosphamide therapy , 2015, Human & experimental toxicology.

[73]  C. Moraes,et al.  Mechanisms linking mtDNA damage and aging. , 2013, Free radical biology & medicine.

[74]  Abbas Ali Mahdi,et al.  PI3K/PTEN/Akt and TSC/mTOR signaling pathways, ovarian dysfunction, and infertility: an update. , 2014, Journal of molecular endocrinology.

[75]  M. Czaja,et al.  Regulation of the effects of CYP2E1-induced oxidative stress by JNK signaling , 2014, Redox biology.

[76]  Richard A. Anderson,et al.  Docetaxel induces moderate ovarian toxicity in mice, primarily affecting granulosa cells of early growing follicles , 2014, Molecular human reproduction.

[77]  S. Horwitz,et al.  Nature as a remarkable chemist: a personal story of the discovery and development of Taxol , 2014, Anti-cancer drugs.

[78]  E. Niki Role of vitamin E as a lipid-soluble peroxyl radical scavenger: in vitro and in vivo evidence. , 2014, Free radical biology & medicine.

[79]  A. Pandey,et al.  Chemistry and Biological Activities of Flavonoids: An Overview , 2013, TheScientificWorldJournal.

[80]  K. Brown,et al.  Resveratrol in the management of human cancer: how strong is the clinical evidence? , 2013, Annals of the New York Academy of Sciences.

[81]  K. Oktay,et al.  Fertility preservation for patients with cancer: American Society of Clinical Oncology clinical practice guideline update. , 2013, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[82]  Dong Li,et al.  Differentially expressed genes in cisplatin-induced premature ovarian failure in rats. , 2013, Animal reproduction science.

[83]  T. Tulandi,et al.  Fertility Preservation Options After Gonadotoxic Chemotherapy , 2013, Clinical medicine insights. Reproductive health.

[84]  Julie Brown,et al.  Antioxidants for female subfertility. , 2013, The Cochrane database of systematic reviews.

[85]  Shaista Malik,et al.  The Sirtuin System: The Holy Grail of Resveratrol? , 2012, Journal of clinical & experimental cardiology.

[86]  J. López-Novoa,et al.  Subcellular targets of cisplatin cytotoxicity: an integrated view. , 2012, Pharmacology & therapeutics.

[87]  Sajal Gupta,et al.  The effects of oxidative stress on female reproduction: a review , 2012, Reproductive Biology and Endocrinology.

[88]  Zeev Blumenfeld,et al.  Chemotherapy and fertility. , 2012, Best practice & research. Clinical obstetrics & gynaecology.

[89]  P. Ray,et al.  Reactive oxygen species (ROS) homeostasis and redox regulation in cellular signaling. , 2012, Cellular signalling.

[90]  E. Chiocca,et al.  Oral tocotrienols are transported to human tissues and delay the progression of the model for end-stage liver disease score in patients. , 2012, The Journal of nutrition.

[91]  E. Perez,et al.  Menstrual history and quality-of-life outcomes in women with node-positive breast cancer treated with adjuvant therapy on the NSABP B-30 trial. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[92]  R. Norman,et al.  The impact of obesity on oocytes: evidence for lipotoxicity mechanisms. , 2011, Reproduction, fertility, and development.

[93]  I. Ben-Aharon,et al.  Doxorubicin-induced apoptosis in germinal vesicle (GV) oocytes. , 2010, Reproductive toxicology.

[94]  Ananda Sen,et al.  Repeat dose study of the cancer chemopreventive agent resveratrol in healthy volunteers: safety, pharmacokinetics, and effect on the insulin-like growth factor axis. , 2010, Cancer research.

[95]  G. Bepler,et al.  Physician referral for fertility preservation in oncology patients: a national study of practice behaviors. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[96]  N. Suzuki,et al.  Ovarian toxicity of paclitaxel and effect on fertility in the rat , 2009, The journal of obstetrics and gynaecology research.

[97]  Michael P. Murphy,et al.  How mitochondria produce reactive oxygen species , 2008, The Biochemical journal.

[98]  U. Luderer,et al.  Cyclophosphamide-induced apoptosis in COV434 human granulosa cells involves oxidative stress and glutathione depletion. , 2007, Toxicological sciences : an official journal of the Society of Toxicology.

[99]  T. A. Santos,et al.  Mitochondrial content reflects oocyte variability and fertilization outcome. , 2006, Fertility and sterility.

[100]  Sajal Gupta,et al.  Role of oxidative stress in female reproduction , 2005, Reproductive biology and endocrinology : RB&E.

[101]  M. Samiec The role of mitochondrial genome [mtDNA] in somatic and embryo cloning of mammals. A review , 2005 .

[102]  K. Conklin Chemotherapy-Associated Oxidative Stress: Impact on Chemotherapeutic Effectiveness , 2004, Integrative cancer therapies.

[103]  P Barrière,et al.  Mitochondrial DNA content affects the fertilizability of human oocytes. , 2001, Molecular human reproduction.

[104]  K. Davies,et al.  Oxidative and non-oxidative mechanisms in the inactivation of cardiac mitochondrial electron transport chain components by doxorubicin. , 1989, The Biochemical journal.

[105]  J. Doroshow,et al.  Redox cycling of anthracyclines by cardiac mitochondria. I. Anthracycline radical formation by NADH dehydrogenase. , 1986, The Journal of biological chemistry.