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Hydrogen sulfide-releasing naproxen suppresses colon cancer cell growth and inhibits NF-κB signaling.

Kodela R, Nath N, Chattopadhyay M, Nesbitt DE, Velázquez-Martínez CA, Kashfi K - Drug Des Devel Ther (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, Pharmacology and Neuroscience, Sophie Davis School of Biomedical Education, City University of New York Medical School, New York, NY, USA.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus

Inhibitory effect of HS-NAP on HT-29 colon cancer cell growth.Notes: (A) The structural components of HS-NAP. (B) Cells were incubated with increasing concentrations of HS-NAP or NAP for 24 hours. Cell viability was determined by MTT assay. The results represent the mean ± standard error of the mean of at least three different experiments with duplicate plates.Abbreviations: HS-NAP, H2S-releasing naproxen; NSAID, nonsteroidal anti-inflammatory drug; NAP, naproxen; IC50, half maximal inhibitory concentration.
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f1-dddt-9-4873: Inhibitory effect of HS-NAP on HT-29 colon cancer cell growth.Notes: (A) The structural components of HS-NAP. (B) Cells were incubated with increasing concentrations of HS-NAP or NAP for 24 hours. Cell viability was determined by MTT assay. The results represent the mean ± standard error of the mean of at least three different experiments with duplicate plates.Abbreviations: HS-NAP, H2S-releasing naproxen; NSAID, nonsteroidal anti-inflammatory drug; NAP, naproxen; IC50, half maximal inhibitory concentration.

Mentions: Our group synthesized the H2S-releasing naproxen (chemical name: 4-(5-thioxo-5H-[1,2]-dithiol-3-yl)-phenyl 2-(6-methoxynaphthalen-2-yl)-propionate, or HS-NAP; Figure 1A), using a previously reported procedure.8 We purchased the parent compound naproxen, along with all other chemicals used in this study, from Sigma-Aldrich (St Louis, MO, USA). We obtained the adenocarcinoma cell line (HT-29, ATCC HTB-38) from the American Type Culture Collection (Manassas, VA, USA). No ethics statement was required from the institutional review board for the use of these cell lines. We conducted the cell proliferation inhibition experiments using McCoy’s 5A medium, supplemented with 10% heat-inactivated fetal calf serum, 2 mmol/L l-glutamine, and a mixture of penicillin/streptomycin (100 units/mL), at 37°C and in 5% CO2.


Hydrogen sulfide-releasing naproxen suppresses colon cancer cell growth and inhibits NF-κB signaling.

Kodela R, Nath N, Chattopadhyay M, Nesbitt DE, Velázquez-Martínez CA, Kashfi K - Drug Des Devel Ther (2015)

Inhibitory effect of HS-NAP on HT-29 colon cancer cell growth.Notes: (A) The structural components of HS-NAP. (B) Cells were incubated with increasing concentrations of HS-NAP or NAP for 24 hours. Cell viability was determined by MTT assay. The results represent the mean ± standard error of the mean of at least three different experiments with duplicate plates.Abbreviations: HS-NAP, H2S-releasing naproxen; NSAID, nonsteroidal anti-inflammatory drug; NAP, naproxen; IC50, half maximal inhibitory concentration.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4554424&req=5

f1-dddt-9-4873: Inhibitory effect of HS-NAP on HT-29 colon cancer cell growth.Notes: (A) The structural components of HS-NAP. (B) Cells were incubated with increasing concentrations of HS-NAP or NAP for 24 hours. Cell viability was determined by MTT assay. The results represent the mean ± standard error of the mean of at least three different experiments with duplicate plates.Abbreviations: HS-NAP, H2S-releasing naproxen; NSAID, nonsteroidal anti-inflammatory drug; NAP, naproxen; IC50, half maximal inhibitory concentration.
Mentions: Our group synthesized the H2S-releasing naproxen (chemical name: 4-(5-thioxo-5H-[1,2]-dithiol-3-yl)-phenyl 2-(6-methoxynaphthalen-2-yl)-propionate, or HS-NAP; Figure 1A), using a previously reported procedure.8 We purchased the parent compound naproxen, along with all other chemicals used in this study, from Sigma-Aldrich (St Louis, MO, USA). We obtained the adenocarcinoma cell line (HT-29, ATCC HTB-38) from the American Type Culture Collection (Manassas, VA, USA). No ethics statement was required from the institutional review board for the use of these cell lines. We conducted the cell proliferation inhibition experiments using McCoy’s 5A medium, supplemented with 10% heat-inactivated fetal calf serum, 2 mmol/L l-glutamine, and a mixture of penicillin/streptomycin (100 units/mL), at 37°C and in 5% CO2.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, Pharmacology and Neuroscience, Sophie Davis School of Biomedical Education, City University of New York Medical School, New York, NY, USA.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus