Cisplatin is a chemotherapy agent commonly used to treat a wide variety of cancers. Despite the potential for both severe acute and chronic side effects, it remains a preferred therapeutic option for many malignancies due to its potent anti-tumor activity. Common cisplatin-associated side-effects include acute kidney injury (AKI) and chronic kidney disease (CKD). These renal injuries may cause delays and potentially cessation of cisplatin therapy and have long-term effects on renal function reserve. Thus, developing mechanism-based interventional strategies that minimize cisplatin-associated kidney injury without reducing efficacy would be of great benefit. In addition to its action of cross-linking DNA, cisplatin has been shown to affect mitochondrial metabolism, resulting in mitochondrially derived reactive oxygen species (ROS). Increased ROS formation in renal proximal convoluted tubule cells is associated with cisplatin-induced AKI and CKD. We review the mechanisms by which cisplatin may induce AKI and CKD and discuss the potential of mitochondrial superoxide dismutase mimetics to prevent platinum-associated nephrotoxicity.

Avasopasem manganese enhances tumor cell killing after ablative hypofractionated radiation through the generation of hydrogen peroxide.

Lung cancer, together with head and neck cancer, accounts for more than one-fourth of cancer deaths worldwide. New, non-toxic therapeutic approaches are needed. High-dose IV vitamin C (aka, pharmacological ascorbate; P-AscH⁻) represents a promising adjuvant to radiochemotherapy that exerts its anti-cancer effects via metal-catalyzed oxidation to form H₂O₂. Mn(III)-porphyrins possessing superoxide dismutase (SOD) mimetic activity have been shown to increase the rate of oxidation of AscH⁻, enhancing the anti-tumor effects of AscH⁻ in several cancer types. The current study demonstrates that the Mn(II)-containing pentaazamacrocyclic selective SOD mimetic GC4419 may serve as an AscH⁻/O₂^•− oxidoreductase as evidenced by the increased rate of oxygen consumption, steady-state concentrations of ascorbate radical, and H₂O₂ production in complete cell culture media. GC4419, but not CuZnSOD, was shown to significantly enhance the toxicity of AscH⁻ in H1299, SCC25, SQ20B, and Cal27 cancer cell lines. This enhanced cancer cell killing was dependent upon the catalytic activity of the SOD mimetic and the generation of H₂O₂, as determined using conditional overexpression of catalase in H1299T cells. GC4419 combined with AscH⁻ was also capable of enhancing radiation-induced cancer cell killing. Currently, AscH⁻ and GC4419 are each being tested separately in clinical trials in combination with radiation therapy. Data presented here support the hypothesis that the combination of GC4419 and AscH⁻ may provide an effective means by which to further enhance radiation therapy responses.

Differences in cancer and normal cell oxidative metabolism provide a unique therapeutic opportunity for developing combined modality approaches with redox-active small molecules as radio-chemosensitizers that are well-tolerated by normal tissues. Pentaazamacrocyclic Mn (II)-containing (MnPAM) superoxide dismutase (SOD) mimetics and pharmacological ascorbate given IV to achieve [mM] plasma levels (pharmacological ascorbate: P-AscH‾) have been shown to act individually as cancer cell radio- and chemosensitizers via the generation of H₂O₂in vivo. The current study shows that the combination of newly developed MnPAM dismutase mimetic, rucosopasem manganese (RUC) with P-AscH‾ radio-sensitizes non-small cell lung cancer cells (NSCLC) and increases steady state levels of intracellular H₂O₂ with no additional toxicity to normal human bronchial epithelial cells (HBECs). Conditional over expression of catalase (CAT) in H1299T CATc15 cells demonstrates that the combination of RUC and P-AscH‾ causes radio-sensitization through an H₂O₂-dependent mechanism. Interestingly, RUC combined with P-AscH‾ demonstrates more than additive cytotoxicity in both H1299T and A549 NSCLC cells, but conditional over-expression of ferritin heavy chain (FtH) protected only the H1299T, and not the A549, from this toxicity. Most importantly, the combination of RUC + P-AscH‾ was found to sensitize both H1299T and A549 cell types to radio-chemotherapy with cisplatin (CIS) + etoposide (ETOP). Finally, in H1299T NSCLC xenografts the combination of RUC + P-AscH‾ with CIS + ETOP and 12 × 2 Gy radiation significantly inhibits tumor growth and increased median overall over survival. These results support the hypothesis that selective MnPAM dismutase mimetic + P-AscH‾ enhances the efficacy of radio-chemotherapy in NSCLC through a mechanism governed by redox active metals and H₂O₂ production.

Background: Therapeutic ionizing radiation is a standard treatment modality for thoracic cancers that may affect surrounding normal tissues, including the cardiovascular system. The increasing recognition of mitochondrial health in cellular responses to oxidative stress, particularly in ionizing radiation‐induced cardiac implications, highlights mitochondria as a critical target for therapeutic interventions. Optimizing mitochondrial function to attenuate ionizing radiation‐induced cardiac pathology necessitates balancing killing cancer cells with sparing nonmalignant tissues. Methods: Using a cardiac targeted radiation injury (CTI) model of injury, C57BL/6J female mice were exposed to a single 16 Gy dose and treated with an SOD (superoxide dismutase) mimetic, ucosopasem manganese (RUC) starting 1 hour before CTI, continued daily for 1 week post CTI, and once per week thereafter until euthanasia to investigate cardiopulmonary implications over 9 months. Results: CTI cardiovascular toxicities were observed in all irradiated mice. RUC significantly increased overall survival and alleviated CTI‐induced changes in cardiac function as assessed by cardiac echocardiography. Persistent changes in mitochondrial oxidative phosphorylation proteins and tricarboxylic acid cycle enzymes were notably attenuated following RUC treatment. Interestingly, RUC reduced both CTI‐induced cardiac fibrosis and the activation of the TGF‐β/Smad (transforming growth factor‐beta/suppressor of mothers against decapentaplegic transcription factor family) pathway. Conclusions: This study presents a novel role for selective superoxide dismutase mimetics, such as RUC, in protecting against CTI‐induced cardiovascular toxicities. As RUC dismutates superoxide, the results suggest superoxide plays a key part in the modulation of mitochondrial oxidative phosphorylation, activation of the canonical TGF‐β/Smad pathway, and ionizing radiation cardiovascular side effects. These findings suggest an association between RUC treatment and TGF‐β pathway antagonism that requires additional mechanistic validation.

Soft tissue sarcomas (STSs) are mesenchymal malignant lesions that develop in soft tissues. Despite current treatments, including radiation therapy (RT) and surgery, STSs can be associated with poor patient outcomes and metastatic recurrences. Neoadjuvant radiation therapy (nRT), while effective, is often accompanied by severe postoperative wound healing complications due to damage to the surrounding normal tissues. Thus, there is a need to develop therapeutic approaches to reduce nRT toxicities. Avasopasem manganese (AVA) is a selective superoxide dismutase mimetic that protects against IR-induced oral mucositis and lung fibrosis. We tested the efficacy of AVA in enhancing RT in STSs and in promoting wound healing. Using colony formation assays and alkaline comet assays, we report that AVA selectively enhanced the STS (liposarcoma, fibrosarcoma, leiomyosarcoma, and MPNST) cellular response to radiation compared to normal dermal fibroblasts (NDFs). AVA is believed to selectively enhance radiation therapy by targeting differential hydrogen peroxide clearance in tumor cells compared to non-malignant cells. STS cells demonstrated increased catalase protein levels and activity compared to normal fibroblasts. Additionally, NDFs showed significantly higher levels of GPx1 activity compared to STSs. The depletion of glutathione using buthionine sulfoximine (BSO) sensitized the NDF cells to AVA, suggesting that GPx1 may, in part, facilitate the selective toxicity of AVA. Finally, AVA significantly accelerated wound closure in a murine model of wound healing post RT. Our data suggest that AVA may be a promising combination strategy for nRT therapy in STSs.