Journal article
Pharmacological ascorbate combined with rucosopasem selectively radio-chemo-sensitizes NSCLC via generation of H 2 O 2
Redox biology, Vol.80, 103505
01/23/2025
DOI: 10.1016/j.redox.2025.103505
PMCID: PMC11830350
PMID: 39884000
Abstract
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 H
O
in 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 H
O
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 H
O
-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 H
O
production.
Details
- Title: Subtitle
- Pharmacological ascorbate combined with rucosopasem selectively radio-chemo-sensitizes NSCLC via generation of H 2 O 2
- Creators
- C F Pulliam - University of IowaM A Fath - University of IowaS Sho - University of IowaS T Johnson - University of IowaB A Wagner - University of IowaM Singhania - University of IowaA L Kalen - University of IowaK Bayanbold - University of IowaS R Solst - University of IowaB G Allen - University of IowaB N George - University of IowaJ M Caster - University of IowaG R Buettner - University of IowaD P Riley - Galera Therapeutics, Malvern, PA, 19355, USA. Electronic address: driley@galeratx.comJ L KeeneR A Beardsley - Galera Therapeutics, Malvern, PA, 19355, USA. Electronic address: rbeardsley@galeratx.comD R Spitz - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Redox biology, Vol.80, 103505
- DOI
- 10.1016/j.redox.2025.103505
- PMID
- 39884000
- PMCID
- PMC11830350
- NLM abbreviation
- Redox Biol
- ISSN
- 2213-2317
- eISSN
- 2213-2317
- Publisher
- ELSEVIER
- Grant note
- National Institutes of Health: T32 CA78586, P01 CA244091, P01 CA217797, P30 CA086862, R50 CA243693 Galera Therapeutics, Inc.
This work was supported by the National Institutes of Health [T32 CA78586, P01 CA244091, P01 CA217797, P30 CA086862, R50 CA243693] , and Galera Therapeutics, Inc.
- Language
- English
- Date published
- 01/23/2025
- Academic Unit
- Stead Family Department of Pediatrics; Pathology; Pharmaceutical Sciences and Experimental Therapeutics; Radiation Oncology; Fraternal Order of Eagles Diabetes Research Center
- Record Identifier
- 9984780351902771
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