H<sub>2</sub>O<sub>2</sub>-Driven Anticancer Activity of Mn Porphyrins and the Underlying Molecular Pathways.
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2021-01
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Mn(III) ortho-N-alkyl- and N-alkoxyalkyl porphyrins (MnPs) were initially developed as superoxide dismutase (SOD) mimics. These compounds were later shown to react with numerous reactive species (such as ONOO-, H2O2, H2S, CO3 •-, ascorbate, and GSH). Moreover, the ability of MnPs to oxidatively modify activities of numerous proteins has emerged as their major mechanism of action both in normal and in cancer cells. Among those proteins are transcription factors (NF-κB and Nrf2), mitogen-activated protein kinases, MAPKs, antiapoptotic bcl-2, and endogenous antioxidative defenses. The lead Mn porphyrins, namely, MnTE-2-PyP5+ (BMX-010, AEOL10113), MnTnBuOE-2-PyP5+ (BMX-001), and MnTnHex-2-PyP5+, were tested in numerous injuries of normal tissue and cellular and animal cancer models. The wealth of the data led to the progression of MnTnBuOE-2-PyP5+ into four Phase II clinical trials on glioma, head and neck cancer, anal cancer, and multiple brain metastases, while MnTE-2-PyP5+ is in Phase II clinical trial on atopic dermatitis and itch.
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Batinic-Haberle, Ines, Artak Tovmasyan, Zhiqing Huang, Weina Duan, Li Du, Sharareh Siamakpour-Reihani, Zhipeng Cao, Huaxin Sheng, et al. (2021). H2O2-Driven Anticancer Activity of Mn Porphyrins and the Underlying Molecular Pathways. Oxidative medicine and cellular longevity, 2021. p. 6653790. 10.1155/2021/6653790 Retrieved from https://hdl.handle.net/10161/23236.
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Scholars@Duke
Ines Batinic-Haberle
A major interest of mine has been in the design and synthesis of Mn porphyrin(MnP)-based powerful catalytic antioxidants which helped establish structure-activity relationship (SAR). It relates the redox property of metalloporphyrins to their ability to remove superoxide. SAR has facilitated the design of redox-active therapeutics and served as a tool for mechanistic considerations. Importantly SAR parallels the magnitude of the therapeutic potential of SOD mimics and is valid for all classes of redox-active compounds. Two lead Mn porphyrins are already in five Phase II clinical trials (reviewed in Batinic-Haberle et al, Oxid Med Cell Longevity 2021). Recent research suggests immense potential of MnPs in cardiac diseases. MnTE-2-PyP (AEOL10113, BMX-010) prevents and treats cardiac arrhythmia, while MnTnBuOE-2-PyP (BMX-001) fully suppressed the development of aortic sclerosis in mice. The latter result is relevant to the cancer patients undergoing chemotherapy. In addition to breast cancer, in collaboration with Angeles Alvarez Secord, MD, MHSc, we have recently shown the anticancer effects of Mn porphyrin/ascorbate in cellular and mouse models of ovarian cancer.
In parallel with synthetic efforts, I have also been interested in the mechanistic aspects of differential actions of Mn porphyrins in normal vs tumor tissue. In-depth studies of chemistry and biology of the reactions of MnPs with redox-active agents relevant to cancer therapy – ascorbate, chemotherapy and radiation – set ground for understanding the role of thermodynamics and kinetics in the mechanism of action of Mn porphyrins. Mechanistic studies have been revealed in Batinic-Haberle et al, Antioxidant Redox Signal 2018, Batinic-Haberle and Tome, Redox Biology 2019 and Batinic-Haberle et al Oxidative Medicine and Cellular Longevity 2021. My research has resulted in over 230 publications, 18 268 citations and an h-index of 64. For my achievements, I have been awarded the 2021 Discovery Award from the Society for Redox Biology and Medicine, SfRBM.
Additional Training
- Postdoctoral fellowship with Professor Alvin Crumbliss in the field of Bioinorganic Chemistry, Department of Chemistry, Duke University
- Postdoctoral fellowship with Professor Irwin Fridovich in the field of Redox Biology, Department of Biochemistry, Duke University School of Medicine
Huaxin Sheng
We have successfully developed various rodent models of brain and spinal cord injuries in our lab, such as focal cerebral ischemia, global cerebral ischemia, head trauma, subarachnoid hemorrhage, intracerebral hemorrhage, spinal cord ischemia, and compression injury. We also established cardiac arrest and hemorrhagic shock models for studying multiple organ dysfunction. Our current studies focus on two projects. One is to examine the efficacy of catalytic antioxidants in treating cerebral ischemia, and the other is to investigate the effectiveness of post-conditioning on the outcome of subarachnoid hemorrhage-induced cognitive dysfunction.
We are a part of the NIH Stroke Preclinical Assessment Network (SPAN).
Ivan Spasojevic
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