Artak Tovmasyan

Suppression of Paclitaxel‐Induced Neuropathy and Ovarian Tumor Growth by Mn Porphyrin, MnTnBuOE‐2‐PyP 5+ (BMX‐001)

Numerous cellular and animal studies demonstrated the ability of redox‐active Mn(III) N ‐alkyl‐ and N ‐alkoxyalkylpyridyporphyrins (MnPs) to protect normal tissue while suppressing tumor growth. The mechanism primarily involves the modulation of NF‐кB and Nrf2 signaling pathways via catalysis of MnP/H 2 O 2 ‐driven protein thiol oxidation. Such differential protection/suppression effects have paved the way of Mn porphyrins (commonly known as mimics of superoxide dismutase) into clinical trials, therefore introducing new line of therapeutics that are affecting cellular redox status/oxidative stress, rather than specific proteins. The most clinically advanced Mn porphyrin, Mn(III) meso ‐tetrakis( N ‐n‐butoxyethyl‐2‐pyridyl) porphyrin (MnTnBuOE‐2‐PyP 5+ , BMX‐001) has progressed into five Phase II clinical trials, two of those related to the injuries of central nervous system. Currently, no efficient treatment for chemotherapy‐induced neuropathy is available in clinics. We therefore employed BMX‐001 to assess its effect on paclitaxel (PTX)‐induced neuropathy. Mechanical (Von‐Frey filaments) and thermal (hot plate) stimulation, toxicity (body weight), muscular coordination and general physical condition (rotarod) of female CD‐1 mice were evaluated over 3 weeks with 2 mg/kg daily dosing and also at clinically relevant dosing of 0.8 mg/kg given subcutaneously (SC) twice weekly after 1.6 mg/kg loading dose. Data revealed a significant ability of BMX‐001 to suppress peripheral neuropathy and neuroinflammation. Importantly, while protecting peripheral tissue, BMX‐001 suppressed the tumor growth of CAOV2 high‐grade serous ovarian cancer in a mouse subcutaneous xenograft model. Previously, the strong anticancer effect was only seen when Mn porphyrins were combined with radiation, chemotherapy, and ascorbate (Asc). Our data further demonstrate that high‐grade serous ovarian cancer is the first in vivo cancer thus far studied where redox‐active Mn porphyrin, as a single agent, exhibits strong anticancer effect, comparable to that of PTX. The effect is presumably due to high tumor levels of BMX‐001 and high oxidative stress specific to the aggressive chemoresistant CAOV2 cell line. Such a strong anticancer effect of BMX‐001 would allow for lowering the dosing of PTX and reducing the neuropathy. The combined neuropathy protection and anticancer efficacy demonstrate, therefore, strong therapeutic potential of BMX‐001 for gynecological cancers. Moreover, the ability of BMX‐001 to suppress neuropathy may be relevant for all types of cancer where chemotherapeutics that induce neuropathy are used as a standard‐of‐care.

A Redox‐active Mn Porphyrin, MnTnBuOE‐2‐PyP5+, Synergizes with Carboplatin in Treatment of Chemoresistant Ovarian Cell Line

We have employed a redox‐active MnP (MnTnBuOE‐2‐PyP5+, Mn(III) meso‐tetrakis (N‐n‐butoxyethylpyridinium‐2‐yl) porphyrin) frequently identified as superoxide dismutase mimic or BMX‐001, to explore the redox status of normal ovarian cell in relation to two ovarian cancer cell lines: OV90 human serous ovarian cancer cell and chemotherapy‐resistant OV90 cell (OVCD). We identified that OVCD cells are under oxidative stress due to high hydrogen peroxide (H2O2) levels and low glutathione peroxidase and thioredoxin 1. Furthermore, OVCD cells have increased glycolysis activity and mitochondrial respiration when compared to immortalized ovarian cells (hTER7) and parental cancer cells (OV90). Our goal was to study how ovarian cell growth depends upon the redox state of the cell; hence, we used MnP (BMX‐001), a redox‐active MnSOD mimetic, as a molecular tool to alter ovarian cancer redox state. Interestingly, OVCD cells preferentially uptake MnP relative to OV90 cells which led to increased inhibition of cell growth, glycolytic activity, OXPHOS, and ATP, in OVCD cells. These effects were further increased when MnP was combined with carboplatin. The effects were discussed with regard to the elevation in H2O2 levels, increased oxidative stress, and reduced Nrf2 levels and its downstream targets when cells were exposed to either MnP or MnP/carboplatin. It is significant to emphasize that MnP protects normal ovarian cell line, hTER7, against carboplatin toxicity. Our data demonstrate that the addition of MnP‐based redox‐active drugs may be used (via increasing excessively the oxidative stress of serous ovarian cancer cells) to improve cancer patients’ chemotherapy outcomes, which develop resistance to platinum‐based drugs.