Redox biology · 2015
Utility Of Nitric Oxide And Hydrogen Sulfide-Releasing Chimeras As Anticancer Agents.
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Kashfi Khosrow
Аннотация
BACKGROUND: Aspirin is chemopreventive but has significant side effects. We developed NOSH-aspirin a safer, nitric oxide and hydrogen sulfide releasing hybrid.
AIM: Here we report on NOSH-aspirin as an anti-inflammatory and its effects on human cancer cell kinetics and various cancer xenografts.
METHODS: Anti-inflammatory: Carageenan rat paw edema model. Cancer cell lines: Colon, HT-29, HCT 15, SW 480; breast, MCF-7, MDA-MB-231; pancreas, MIA PaCa2, BxPC3. Normal cell lines: human mammary, HMEpC; pancreatic epithelial, ACBRI 515. Xenografts: nude mice implanted with HT-29, MDA-MB-231, MIA PaCa2 cells, were treated with NOSH-aspirin (100mg/kg/d) or vehicle. After 3 weeks, mice were sacrificed, tumors excised, weighed, and fixed for IHC studies.
RESULTS: NOSH-aspirin significantly reduced paw edema as function of time. NOSH-aspirin's IC50 in nM at 24h for cell growth inhibition ranged from 50±2 to 250±10 in the cancer cell lines and about 400-fold higher in the normal cell lines. The cell growth inhibitory effects were due to a dose-dependent induction of apoptosis and cell cycle arrest (G0/G1), leading to reductions in cell proliferation. In xenografts, NOSH-aspirin had no effect on the weight of the mice. Tumor volume was reduced as a function of treatment time. At sacrifice, tumor mass reductions were colon: 89%, P=0.005; breast: 91%, P=0.006; pancreas: 75%, P=0.0031. Growth inhibition was due to reduced proliferation (decreased PCNA expression), and induction of apoptosis (increased TUNEL positive cells).
CONCLUSIONS: NOSH-aspirin is a potent anti-inflammatory, preferentially affecting cancer cells and targets parameters important in determining cellular mass.
AIM: Here we report on NOSH-aspirin as an anti-inflammatory and its effects on human cancer cell kinetics and various cancer xenografts.
METHODS: Anti-inflammatory: Carageenan rat paw edema model. Cancer cell lines: Colon, HT-29, HCT 15, SW 480; breast, MCF-7, MDA-MB-231; pancreas, MIA PaCa2, BxPC3. Normal cell lines: human mammary, HMEpC; pancreatic epithelial, ACBRI 515. Xenografts: nude mice implanted with HT-29, MDA-MB-231, MIA PaCa2 cells, were treated with NOSH-aspirin (100mg/kg/d) or vehicle. After 3 weeks, mice were sacrificed, tumors excised, weighed, and fixed for IHC studies.
RESULTS: NOSH-aspirin significantly reduced paw edema as function of time. NOSH-aspirin's IC50 in nM at 24h for cell growth inhibition ranged from 50±2 to 250±10 in the cancer cell lines and about 400-fold higher in the normal cell lines. The cell growth inhibitory effects were due to a dose-dependent induction of apoptosis and cell cycle arrest (G0/G1), leading to reductions in cell proliferation. In xenografts, NOSH-aspirin had no effect on the weight of the mice. Tumor volume was reduced as a function of treatment time. At sacrifice, tumor mass reductions were colon: 89%, P=0.005; breast: 91%, P=0.006; pancreas: 75%, P=0.0031. Growth inhibition was due to reduced proliferation (decreased PCNA expression), and induction of apoptosis (increased TUNEL positive cells).
CONCLUSIONS: NOSH-aspirin is a potent anti-inflammatory, preferentially affecting cancer cells and targets parameters important in determining cellular mass.