Hydrogen sulfide-releasing naproxen suppresses colon cancer cell growth and inhibits NF-κB signaling.
Colorectal cancer (CRC) is the second leading cause of death due to cancer and the third most common cancer in men and women in the USA. Nuclear factor kappa B (NF-κB) is known to be activated in CRC and is strongly implicated in its development and progression. Therefore, activated NF-κB constitutes a bona fide target for drug development in this type of malignancy. Many epidemiological and interventional studies have established nonsteroidal anti-inflammatory drugs (NSAIDs) as a viable chemopreventive strategy against CRC. Our previous studies have shown that several novel hydrogen sulfide-releasing NSAIDs are promising anticancer agents and are safer derivatives of NSAIDs. In this study, we examined the growth inhibitory effect of a novel H2S-releasing naproxen (HS-NAP), which has a repertoire as a cardiovascular-safe NSAID, for its effects on cell proliferation, cell cycle phase transitions, and apoptosis using HT-29 human colon cancer cells. We also investigated its effect as a chemo-preventive agent in a xenograft mouse model. HS-NAP suppressed the growth of HT-29 cells by induction of G0/G1 arrest and apoptosis and downregulated NF-κB. Tumor xenografts in mice were significantly reduced in volume. The decrease in tumor mass was associated with a reduction of cell proliferation, induction of apoptosis, and decreases in NF-κB levels in vivo. Therefore, HS-NAP demonstrates strong anticancer potential in CRC.
Department of Physiology, Pharmacology and Neuroscience, Sophie Davis School of Biomedical Education, City University of New York Medical School, New York, NY, USA.
Ravinder
R
Kodela
Department of Life Sciences, New York Institute of Technology, New York, NY, USA.
Niharika
N
Nath
Department of Physiology, Pharmacology and Neuroscience, Sophie Davis School of Biomedical Education, City University of New York Medical School, New York, NY, USA.
Mitali
M
Chattopadhyay
Department of Physiology, Pharmacology and Neuroscience, Sophie Davis School of Biomedical Education, City University of New York Medical School, New York, NY, USA.
Diandra E
DE
Nesbitt
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada.
Carlos A
CA
Velázquez-Martínez
Department of Physiology, Pharmacology and Neuroscience, Sophie Davis School of Biomedical Education, City University of New York Medical School, New York, NY, USA.
Khosrow
K
Kashfi
D000818:Animals; D016588:Anticarcinogenic Agents / Q000378:metabolism / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D004305:Dose-Response Relationship, Drug; D019073:HT29 Cells; D006801:Humans; D006862:Hydrogen Sulfide / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D008819:Mice, Nude; D016328:NF-kappa B / Q000378:metabolism*; D009288:Naproxen / Q000378:metabolism / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D013880:Thioredoxin-Disulfide Reductase / Q000378:metabolism; D013997:Time Factors; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D016588:Anticarcinogenic Agents; D016328:NF-kappa B; D009288:Naproxen; D013880:Thioredoxin-Disulfide Reductase; D006862:Hydrogen Sulfide
NF-κB; apoptosis; cell cycle; chemoprevention; nonsteroidal anti-inflammatory drugs; thioredoxin reductase; xenograft