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Inhibition of midkine by metformin can contribute to its anticancer effects in malignancies: A proposal mechanism of action of metformin in context of endometrial cancer prevention and therapy.
Med Hypotheses 2019; 134:109420MH

Abstract

Metformin, a drug widely used in the treatment of type II diabetes mellitus (T2DM), has been the focus of interest as a potential therapeutic agent for certain types of malignancies, including gynaecological cancers [i.e. endometrial cancer (EC)]. Although the exact mechanism behind the potential anticancer activity of metformin is still not completely understood, certain studies have suggested that different effects on cell functions, such as inhibition of cell migration, apoptosis and tumor cell proliferation, are involved in its preventive and therapeutic effects in certain types of malignancies, including EC. In contrast, midkine (MK), a heparin-binding growth factor and cytokine, which induces carcinogenesis and chemoresistance, promotes the development and progression of many malignant tumours by increasing diverse cell functions such as cell proliferation, cell survival and antiapoptotic activities via mainly the activation of phosphatidyl inositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways. The same pathways are also subject to certain therapeutic effects of metformin, although this cytokine and this drug have some different mechanism of action pathways as well. Taken together, MK and metformin appear to have opposite effects in various biological processes such as apoptosis, cell proliferation, cell survival, cell migration, and angiogenesis. On the other hand, MK activates PI3K and MAPK cell signal pathways, whereas metformin inhibits these two pathways. It seems likely that almost all the pathways and cell functions, which play important roles in malignancies, are inhibited by metformin and activated by MK. Given the opposite relationship between the actions of metformin and MK, we hypothesize that metformin may act like a novel MK inhibitor in some malignancies. We also discuss the possible relationship between metformin and MK in the context of EC, the most common gynecological cancer worldwide, which incidence is rising rapidly, in parallel with the increase in obesity, T2DM and insulin resistance. In this respect, the therapeutic use of metformin may improve the survival of EC or other cancers, via inhibiting or overcoming the unwanted effects of MK in carcinogenesis.

Authors+Show Affiliations

Department of Gynecology and Obstetrics, Istanbul Aydin University, Medical Faculty, Florya Main Campus, Kücükcekmece, 34295 Istanbul, Turkey.Department of Medical Pharmacology, Istanbul Aydin University, Medical Faculty, Florya Main Campus, Kücükcekmece, 34295 Istanbul, Turkey. Electronic address: ahmetaynacioglu@aydin.edu.tr.Department of Histology and Embryology, Istanbul Aydin University, Medical Faculty, Florya Main Campus, Kücükcekmece, 34295 Istanbul, Turkey.Department of Anatomy, Istanbul Aydin University, Medical Faculty, Florya Main Campus, Kücükcekmece, 34295 Istanbul, Turkey.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31634770

Citation

Karadeniz, Zeliha, et al. "Inhibition of Midkine By Metformin Can Contribute to Its Anticancer Effects in Malignancies: a Proposal Mechanism of Action of Metformin in Context of Endometrial Cancer Prevention and Therapy." Medical Hypotheses, vol. 134, 2019, p. 109420.
Karadeniz Z, Aynacıoğlu AŞ, Bilir A, et al. Inhibition of midkine by metformin can contribute to its anticancer effects in malignancies: A proposal mechanism of action of metformin in context of endometrial cancer prevention and therapy. Med Hypotheses. 2019;134:109420.
Karadeniz, Z., Aynacıoğlu, A. Ş., Bilir, A., & Tuna, M. Y. (2019). Inhibition of midkine by metformin can contribute to its anticancer effects in malignancies: A proposal mechanism of action of metformin in context of endometrial cancer prevention and therapy. Medical Hypotheses, 134, p. 109420. doi:10.1016/j.mehy.2019.109420.
Karadeniz Z, et al. Inhibition of Midkine By Metformin Can Contribute to Its Anticancer Effects in Malignancies: a Proposal Mechanism of Action of Metformin in Context of Endometrial Cancer Prevention and Therapy. Med Hypotheses. 2019 Oct 3;134:109420. PubMed PMID: 31634770.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inhibition of midkine by metformin can contribute to its anticancer effects in malignancies: A proposal mechanism of action of metformin in context of endometrial cancer prevention and therapy. AU - Karadeniz,Zeliha, AU - Aynacıoğlu,A Şükrü, AU - Bilir,Ayhan, AU - Tuna,M Yakup, Y1 - 2019/10/03/ PY - 2019/07/25/received PY - 2019/09/20/revised PY - 2019/09/30/accepted PY - 2019/10/22/pubmed PY - 2019/10/22/medline PY - 2019/10/22/entrez KW - Endometrial cancer KW - Malignancies KW - Metformin KW - Midkine SP - 109420 EP - 109420 JF - Medical hypotheses JO - Med. Hypotheses VL - 134 N2 - Metformin, a drug widely used in the treatment of type II diabetes mellitus (T2DM), has been the focus of interest as a potential therapeutic agent for certain types of malignancies, including gynaecological cancers [i.e. endometrial cancer (EC)]. Although the exact mechanism behind the potential anticancer activity of metformin is still not completely understood, certain studies have suggested that different effects on cell functions, such as inhibition of cell migration, apoptosis and tumor cell proliferation, are involved in its preventive and therapeutic effects in certain types of malignancies, including EC. In contrast, midkine (MK), a heparin-binding growth factor and cytokine, which induces carcinogenesis and chemoresistance, promotes the development and progression of many malignant tumours by increasing diverse cell functions such as cell proliferation, cell survival and antiapoptotic activities via mainly the activation of phosphatidyl inositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways. The same pathways are also subject to certain therapeutic effects of metformin, although this cytokine and this drug have some different mechanism of action pathways as well. Taken together, MK and metformin appear to have opposite effects in various biological processes such as apoptosis, cell proliferation, cell survival, cell migration, and angiogenesis. On the other hand, MK activates PI3K and MAPK cell signal pathways, whereas metformin inhibits these two pathways. It seems likely that almost all the pathways and cell functions, which play important roles in malignancies, are inhibited by metformin and activated by MK. Given the opposite relationship between the actions of metformin and MK, we hypothesize that metformin may act like a novel MK inhibitor in some malignancies. We also discuss the possible relationship between metformin and MK in the context of EC, the most common gynecological cancer worldwide, which incidence is rising rapidly, in parallel with the increase in obesity, T2DM and insulin resistance. In this respect, the therapeutic use of metformin may improve the survival of EC or other cancers, via inhibiting or overcoming the unwanted effects of MK in carcinogenesis. SN - 1532-2777 UR - https://www.unboundmedicine.com/medline/citation/31634770/Inhibition_of_midkine_by_metformin_can_contribute_to_its_anticancer_effects_in_malignancies:_A_proposal_mechanism_of_action_of_metformin_in_context_of_endometrial_cancer_prevention_and_therapy L2 - https://linkinghub.elsevier.com/retrieve/pii/S0306-9877(19)30779-0 DB - PRIME DP - Unbound Medicine ER -