BMX-001 as a Therapeutic for Preventing Chemotherapy-Induced Neuropathic Pain

Introduction: : Chemotherapy-induced neuropathic pain (CINP) remains a major unmet challenge and a significant dose-limiting adverse effect of chemotherapeutic agents during cancer treatment, which severely limits therapeutic compliance and compromises quality of life for patients. Although chemotherapeutic agents such as paclitaxel (PTX) demonstrate potent antitumor effects, they often induce progressive neurotoxicity that leads to mechanical allodynia, thermal hyperalgesia, and chronic sensory disturbances. Although anticonvulsants and antidepressants have been used in current treatments, they focus on temporary relief of symptoms of CINP instead of preventing the underlying peripheral neuropathy. At this time, no effective clinical therapies could directly target this underlying nerve damage. Oxidative stress and neuroinflammation have been known to play roles in CINP. BMX-001 is a redox-active manganese metalloporphyrin that mimics superoxide dismutase activity. It has emerged as a potential candidate that can keep the integrity of normal cells under oxidative stress instead of tumors. Although it has been demonstrated that BMX-001 reduces ROS accumulation and suppresses inflammatory cytokine expression in peripheral nerves and dorsal root ganglia (DRGs), its efficacy and mechanism in preventing CINP and its impact on normal cells versus tumor cells still requires further validation. This study investigated BMX-001’s dual role in stabilizing satellite glial cells (SGCs) while inhibiting breast cancer cells MDA-MB-231 during PTX treatment in vitro and evaluated the neuroprotective role of BMX-001 in CINP in vivo.

Materials and

Methods: : Primary SGCs were isolated from L4–L5 DRGs of C57BL/6 mice. PTX and BMX-001 were used to treat SGCs and MDA-MB-231 breast cancer cells to measure their effects on ROS generation by H2DCFDA staining (Figure 1A-B). Female C57BL/6 mice of 56–62 days old were randomly assigned to one of 3 groups in vivo: Sham, PTX injection, PTX+BMX-001 injection. We developed a mouse CINP model by i.p. injection of PTX on four alternate days (day 1, 3, 5, and 7) at a dose of 8 mg/kg, so as to reach a cumulative dose of 32 mg/kg. BMX-001 was administered via subcutaneous injection at a dose of 0.5 mg/kg. Behavioral testing of mice was evaluated by von Frey filament assay for mechanical allodynia, acetone drop test for cold allodynia, and hot plate test for thermal hyperalgesia (Figure 1G-I). DRGs, sciatic nerves, and hind paw tissues were collected for qPCR analysis (TNF-α, IL-6, Nrf2, and TRPV1) (Figure 1C-D) and immunofluorescence staining (TRPV1, TNF-α, and Iba-1) (Figure 1E-F).

Results, Conclusions, and Discussions:: According to our in vitro findings, BMX-001 intensified ROS stress in MDA-MB-231 cancer cells while reducing PTX-induced ROS accumulation in SGCs, suggesting a differential redox impact of BMX-001 (Figure 1A-B). Co-treatment with BMX-001 dramatically decreased PTX-elevated pro-inflammatory TNF-α levels and increased Nrf2 in SGCs (Figure 1C-D). On the other hand, BMX-001 did not inhibit TNF-α production in MDA-MB-231 cells and further reduced the activity of antioxidant enzymes, indicating that its pro-oxidant function might enhance the tumoricidal synergy with PTX. According to the behavioral tests conducted in vivo, BMX-001 alleviated mechanical and cold allodynia in CINP mice (Figure 1G-I). In the DRGs of mice treated with PTX, a hyperexcitability marker, TRPV1 (Figure 1E), and pro-inflammatory cytokines, including TNF-α and IL-6, were markedly increased (Figure 1C-D). However, this was reversed by the administration of BMX-001. Reduced peripheral inflammation was shown by lower Iba-1 expression, indicating decreased macrophage infiltration (Figure 1F). In DRG tissues, BMX-001 also preserved antioxidant defenses and increased Nrf2 expression. In treated mice, these changes were associated with restored pain thresholds. In summary, our study identified BMX-001 as a potential neuroprotective chemotherapeutic adjuvant without tumor-enhancing activity. This translational potential is demonstrated by its capacity in controlling neuroinflammation and oxidative damage while maintaining cancer cell cytotoxicity. For future research, to improve drug accumulation at targeted sites and thus enhance neuropathic pain relief, we may potentially integrate a novel double-layered microneedle with a drug-loading tip layer for rapid release and a supporting layer for mechanical insertion to deliver BMX-001 effectively into skin containing peripheral nerve endings.

Acknowledgements and/or References (Optional):: UN Collaboration Initiative Grant, LB606 Nebraska Stem Cell Grant, UNMC Center for Drug Design and Innovation (CDDI) Seed Grant, NIH R21CA298918