Limits...
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

HS-NAP inhibits proliferation by altering cell cycle progression and inducing apoptosis.Notes: Cells were treated with vehicle, 0.5× IC50 (36 µM), 1× IC50 (72 µM) or 2× IC50 (144 µM) HS-NAP for 24 hours and analyzed for (A) proliferation by PCNA expression; (B) cell cycle phases by PI staining and flow cytometry; (C) apoptosis by Annexin V staining and flow cytometry. In (A and C), the results are shown as the mean ± standard error of the mean for three different experiments performed in duplicate. *P<0.05 and **P<0.01 compared with control. In (B), the results are representative of two different experiments.Abbreviations: HS-NAP, H2S-releasing naproxen; PI, propidium iodide; PCNA, proliferating cell nuclear antigen; IC50, half maximal inhibitory concentration.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4554424&req=5

f2-dddt-9-4873: HS-NAP inhibits proliferation by altering cell cycle progression and inducing apoptosis.Notes: Cells were treated with vehicle, 0.5× IC50 (36 µM), 1× IC50 (72 µM) or 2× IC50 (144 µM) HS-NAP for 24 hours and analyzed for (A) proliferation by PCNA expression; (B) cell cycle phases by PI staining and flow cytometry; (C) apoptosis by Annexin V staining and flow cytometry. In (A and C), the results are shown as the mean ± standard error of the mean for three different experiments performed in duplicate. *P<0.05 and **P<0.01 compared with control. In (B), the results are representative of two different experiments.Abbreviations: HS-NAP, H2S-releasing naproxen; PI, propidium iodide; PCNA, proliferating cell nuclear antigen; IC50, half maximal inhibitory concentration.

Mentions: We observed that HS-NAP reduced PCNA expression in HT-29 cells in a dose-dependent manner. In this regard, the magnitude of reduction was 29%±3% at 36 µM, 51%±5% at 72 µM, and 74%±4% at 144 µM (Figure 2A). Likewise, we observed that HS-NAP caused a concentration-dependent accumulation of HT-29 cells in the G0/G1 phase (Figure 2B), while fewer cells were in S and G2/M phases. HS-NAP increased the population of cells in G0/G1 phase from 37.2% (control cells) to 48.8%, 69.7%, and 77.3% at 36, 72, and 144 µM, respectively. The population of cells in the S phase also decreased from 40.9% in control cells to 32.0% (at 36 µM), 17.7% (at 72 µM), and 13.3% (at 144 µM). Finally, we also observed a decrease in the number of cells in the G2/M phase as a result of incubation of HT-29 cells with increasing concentrations of HS-NAP; in this regard, we calculated that approximately 21.9% of cells were in the G2/M phase when no drug was added (control), but this changed to 19.2% (at 36 µM), 12.6% (at 72 µM), and 9.4% (at 144 µM).


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)

HS-NAP inhibits proliferation by altering cell cycle progression and inducing apoptosis.Notes: Cells were treated with vehicle, 0.5× IC50 (36 µM), 1× IC50 (72 µM) or 2× IC50 (144 µM) HS-NAP for 24 hours and analyzed for (A) proliferation by PCNA expression; (B) cell cycle phases by PI staining and flow cytometry; (C) apoptosis by Annexin V staining and flow cytometry. In (A and C), the results are shown as the mean ± standard error of the mean for three different experiments performed in duplicate. *P<0.05 and **P<0.01 compared with control. In (B), the results are representative of two different experiments.Abbreviations: HS-NAP, H2S-releasing naproxen; PI, propidium iodide; PCNA, proliferating cell nuclear antigen; IC50, half maximal inhibitory concentration.
© Copyright Policy
Related In: Results  -  Collection

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

f2-dddt-9-4873: HS-NAP inhibits proliferation by altering cell cycle progression and inducing apoptosis.Notes: Cells were treated with vehicle, 0.5× IC50 (36 µM), 1× IC50 (72 µM) or 2× IC50 (144 µM) HS-NAP for 24 hours and analyzed for (A) proliferation by PCNA expression; (B) cell cycle phases by PI staining and flow cytometry; (C) apoptosis by Annexin V staining and flow cytometry. In (A and C), the results are shown as the mean ± standard error of the mean for three different experiments performed in duplicate. *P<0.05 and **P<0.01 compared with control. In (B), the results are representative of two different experiments.Abbreviations: HS-NAP, H2S-releasing naproxen; PI, propidium iodide; PCNA, proliferating cell nuclear antigen; IC50, half maximal inhibitory concentration.
Mentions: We observed that HS-NAP reduced PCNA expression in HT-29 cells in a dose-dependent manner. In this regard, the magnitude of reduction was 29%±3% at 36 µM, 51%±5% at 72 µM, and 74%±4% at 144 µM (Figure 2A). Likewise, we observed that HS-NAP caused a concentration-dependent accumulation of HT-29 cells in the G0/G1 phase (Figure 2B), while fewer cells were in S and G2/M phases. HS-NAP increased the population of cells in G0/G1 phase from 37.2% (control cells) to 48.8%, 69.7%, and 77.3% at 36, 72, and 144 µM, respectively. The population of cells in the S phase also decreased from 40.9% in control cells to 32.0% (at 36 µM), 17.7% (at 72 µM), and 13.3% (at 144 µM). Finally, we also observed a decrease in the number of cells in the G2/M phase as a result of incubation of HT-29 cells with increasing concentrations of HS-NAP; in this regard, we calculated that approximately 21.9% of cells were in the G2/M phase when no drug was added (control), but this changed to 19.2% (at 36 µM), 12.6% (at 72 µM), and 9.4% (at 144 µM).

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