# Exploiting multidrug resistance mechanisms to counter radiation toxicity

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2021 · $381,076

## Abstract

PROJECT SUMMARY/ABSTRACT
Unanticipated exposure to ionizing radiation (IR) is a clear and present risk due to unpredictable natural
catastrophes near nuclear power plants and heightened global terrorist activities, as well as to
medical radiological errors and machine malfunctions. Currently, no effective method exits to treat
the potentially thousands of victims during a radiological event. The ideal treatment would be one that
could be administered at least 24 hrs after exposure as a pill or injectable. A major obstacle to
designing such a pharmaceutical is the lack of a molecular pathway to specifically target. A recent
high-throughput screening (HTS) discovery project of small-molecule libraries uncovered a family of
promising radiomitigators possessing a nitrophenylsulfonamide (NPS) core. Unfortunately, their
mechanism of action in mitigating radiation toxicity is unknown. Serendipitously during an unrelated
study on glutathione (GSH) efflux from irradiated cells via multidrug resistance transport (MRT), it
was realized that inhibitors of MRT share the NPS chemical structure found in the screened
radiomitigators. Because active efflux of GSH and GSH-conjugated molecules is a critical
determinant of cell death, a novel idea arose connecting one study with the other. The hypothesis to be
tested in this proposal is that inhibition of MRT mediated GSH efflux following IR will rescue cells from
death, mitigating acute radiation toxicity. The radiomitigating NPS drugs selected from the HTS and
known MRT inhibitors will be used to investigate the following specific aims: 1) Establish importance of
GSH efflux and cell death kinetics post-IR, 2) Establish MRT as a mediator of IR-induced cell death and
as a target for mitigation, 3) Optimize administration of GSH efflux/MRT inhibitor 24h or more after
irradiation, and 4) determine differential effects of GSH efflux/MRT inhibitors on hematopoietic
and gastrointestinal tissues to target mitigation of organ-specific radiation syndromes. The
milestones will be the identification of a link between MRT-mediated GSH efflux and radiation-induced
death, discovery of a set of unique tissue-specific targets for mitigating acute radiation toxicity, and
establishment of a basis to develop accessible pharmaceuticals for wide dispersal during a catastrophic
radiological event.

## Key facts

- **NIH application ID:** 10212220
- **Project number:** 5R01AI128739-05
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Keisuke S. Iwamoto
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $381,076
- **Award type:** 5
- **Project period:** 2017-08-07 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10212220

## Citation

> US National Institutes of Health, RePORTER application 10212220, Exploiting multidrug resistance mechanisms to counter radiation toxicity (5R01AI128739-05). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10212220. Licensed CC0.

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