ROS-activatable prodrug of doxazolidine as novel cancer therapy paradigm Journal Article
| Authors: | Tamura, R.; Carpenter, C. I.; Thomas, C. M.; Kamyabi, G.; Hsu, H. T.; Vergnolle, O.; Balderes, P.; Grimm, J. |
| Article Title: | ROS-activatable prodrug of doxazolidine as novel cancer therapy paradigm |
| Abstract: | Overcoming severe side effects from anticancer agents without decreasing their effects on tumor growth is a major challenge. A prodrug technology is reported using agents that are spatiotemporally activated primarily in tumors while the extratumoral toxicity to healthy cells is minimized. A ROS-activatable prodrug of a strong anticancer agent, doxazolidine (doxaz), is developed. Doxaz is a DNA alkylating agent with a half-life of 3 min and significantly higher cytotoxicity than the clinically used parental compound doxorubicin (dox). Importantly, doxaz is not affected by p-glycoprotein expression since it irreversibly alkylates DNA while dox inhibits the topoisomerase II DNA complex. As drug activators, reactive oxygen species (ROS) are already produced inside cancer cells in higher abundance than in normal cells but additionally generated by external stimuli such as radionuclides (via radiolysis of water) and/or ROS-inducing drugs. We synthesized the prodrug, Doxaz-BA, and evaluated its efficacy in vitro in cell cultures and then in vivo in xenograft mouse models. Doxaz-BA is effective in a broad range of cancer cells since most cancer cells produce higher levels of ROS. Combining with clinically relevant radiotracers such as 18F-FDG or other tumor-tropic agents / ROS inducing drugs results in a tumor-specific and enhanced localized therapy paradigm. © 2024 Wiley-VCH GmbH. |
| Keywords: | controlled study; protein expression; unclassified drug; human cell; sorafenib; doxorubicin; drug efficacy; nonhuman; chemotherapy; animal cell; mouse; animal experiment; animal model; alkylating agent; in vivo study; in vitro study; tumor xenograft; drug resistance; drug synthesis; cancer therapy; radiology; fluorodeoxyglucose f 18; reactive oxygen metabolite; nanoparticle; alkylation; trastuzumab; dna topoisomerase (atp hydrolysing); imidazole derivative; prodrug; radiolysis; ketone derivative; radionuclides; cancer; human; article; dna alkylation; antibody drug conjugate; abc transporter subfamily b; imidazole ketone erastin; doxazolidine; doxazolidine boronic acid |
| Journal Title: | Advanced Therapeutics |
| Volume: | 7 |
| Issue: | 12 |
| ISSN: | 2366-3987 |
| Publisher: | Wiley Blackwell |
| Date Published: | 2024-12-01 |
| Start Page: | 2400340 |
| Language: | English |
| DOI: | 10.1002/adtp.202400340 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledge in the PDF -- Corresponding authors is MSK authors: Jan Grimm -- Source: Scopus |
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