High-Dose Acetaminophen as a Treatment for Cancer
The use of high-dose acetaminophen (AAP) with n-acetylcysteine (NAC) rescue was studied as an anti-cancer treatment in phase I trials with promising signals of anti-tumor efficacy. Correlative analysis suggested that AAP has a free-radical-independent mechanism of anti-tumor activity—in contrast to...
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| Format: | Article |
| Language: | English |
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MDPI AG
2024-01-01
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| Series: | Livers |
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| Online Access: | https://www.mdpi.com/2673-4389/4/1/7 |
| _version_ | 1797240266263887872 |
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| author | Jeffrey Wu Bradley Maller Rujul Kaul Andrea Galabow Allyn Bryan Alexander Neuwelt |
| author_facet | Jeffrey Wu Bradley Maller Rujul Kaul Andrea Galabow Allyn Bryan Alexander Neuwelt |
| author_sort | Jeffrey Wu |
| collection | DOAJ |
| description | The use of high-dose acetaminophen (AAP) with n-acetylcysteine (NAC) rescue was studied as an anti-cancer treatment in phase I trials with promising signals of anti-tumor efficacy. Correlative analysis suggested that AAP has a free-radical-independent mechanism of anti-tumor activity—in contrast to the well-established mechanism of AAP hepatotoxicity. Subsequent “reverse translational” studies in the pre-clinical setting have identified novel mechanisms of action of high-dose AAP, including modulation of JAK-STAT signaling in both the tumor cell and the tumor immune microenvironment. Importantly, these effects are free-radical-independent and not reversed by concurrent administration of the established AAP rescue agents fomepizole and NAC. By administering high-dose AAP concurrently with fomepizole and NAC, 100-fold higher AAP levels than those of standard dosing can be achieved in mice without detected toxicity and with substantial anti-tumor efficacy against commonly used mouse models of lung and breast cancer that are resistant to standard first-line anti-cancer therapies. With these recent advances, additional clinical trials of high-dose AAP with concurrent NAC and fomepizole-based rescue are warranted. |
| first_indexed | 2024-04-24T18:04:42Z |
| format | Article |
| id | doaj.art-570694b97bca4144a2b354e7774223fa |
| institution | Directory Open Access Journal |
| issn | 2673-4389 |
| language | English |
| last_indexed | 2024-04-24T18:04:42Z |
| publishDate | 2024-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Livers |
| spelling | doaj.art-570694b97bca4144a2b354e7774223fa2024-03-27T13:51:32ZengMDPI AGLivers2673-43892024-01-0141849310.3390/livers4010007High-Dose Acetaminophen as a Treatment for CancerJeffrey Wu0Bradley Maller1Rujul Kaul2Andrea Galabow3Allyn Bryan4Alexander Neuwelt5Department of Neurology, School of Medicine, Oregon Health and Sciences University, 3181 Sam Jackson Park Rd., Portland, OR 97239, USADepartment of Veterans Affairs, 1201 Broad Rock Blvd, Richmond, VA 23249, USADepartment of Veterans Affairs, 1201 Broad Rock Blvd, Richmond, VA 23249, USADepartment of Veterans Affairs, 1201 Broad Rock Blvd, Richmond, VA 23249, USADepartment of Veterans Affairs, 1201 Broad Rock Blvd, Richmond, VA 23249, USADepartment of Veterans Affairs, 1201 Broad Rock Blvd, Richmond, VA 23249, USAThe use of high-dose acetaminophen (AAP) with n-acetylcysteine (NAC) rescue was studied as an anti-cancer treatment in phase I trials with promising signals of anti-tumor efficacy. Correlative analysis suggested that AAP has a free-radical-independent mechanism of anti-tumor activity—in contrast to the well-established mechanism of AAP hepatotoxicity. Subsequent “reverse translational” studies in the pre-clinical setting have identified novel mechanisms of action of high-dose AAP, including modulation of JAK-STAT signaling in both the tumor cell and the tumor immune microenvironment. Importantly, these effects are free-radical-independent and not reversed by concurrent administration of the established AAP rescue agents fomepizole and NAC. By administering high-dose AAP concurrently with fomepizole and NAC, 100-fold higher AAP levels than those of standard dosing can be achieved in mice without detected toxicity and with substantial anti-tumor efficacy against commonly used mouse models of lung and breast cancer that are resistant to standard first-line anti-cancer therapies. With these recent advances, additional clinical trials of high-dose AAP with concurrent NAC and fomepizole-based rescue are warranted.https://www.mdpi.com/2673-4389/4/1/7acetaminophenN-acetylcysteinefomepizolecancer |
| spellingShingle | Jeffrey Wu Bradley Maller Rujul Kaul Andrea Galabow Allyn Bryan Alexander Neuwelt High-Dose Acetaminophen as a Treatment for Cancer Livers acetaminophen N-acetylcysteine fomepizole cancer |
| title | High-Dose Acetaminophen as a Treatment for Cancer |
| title_full | High-Dose Acetaminophen as a Treatment for Cancer |
| title_fullStr | High-Dose Acetaminophen as a Treatment for Cancer |
| title_full_unstemmed | High-Dose Acetaminophen as a Treatment for Cancer |
| title_short | High-Dose Acetaminophen as a Treatment for Cancer |
| title_sort | high dose acetaminophen as a treatment for cancer |
| topic | acetaminophen N-acetylcysteine fomepizole cancer |
| url | https://www.mdpi.com/2673-4389/4/1/7 |
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