Utility Of Nitric Oxide And Hydrogen Sulfide-Releasing Chimeras As Anticancer Agents.
Aspirin is chemopreventive but has significant side effects. We developed NOSH-aspirin a safer, nitric oxide and hydrogen sulfide releasing hybrid.



Here we report on NOSH-aspirin as an anti-inflammatory and its effects on human cancer cell kinetics and various cancer xenografts.



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.



NOSH-aspirin significantly reduced paw edema as function of time. NOSH-aspirin's IC50in 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).



NOSH-aspirin is a potent anti-inflammatory, preferentially affecting cancer cells and targets parameters important in determining cellular mass.
City University of New York Medical School, New York, USA.
Khosrow
K
Kashfi
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001241:Aspirin / Q000031:analogs & derivatives* / Q000494:pharmacology; D004220:Disulfides / Q000494:pharmacology*; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009566:Nitrates / Q000494:pharmacology*; D009569:Nitric Oxide / Q000494:pharmacology*; D051381:Rats; D023041:Xenograft Model Antitumor Assays
C571898:4-(3-thioxo-3H-1,2-dithiol-5-yl)phenyl 2-((4-(nitrooxy)butanoyl)oxy)benzoate; D000970:Antineoplastic Agents; D004220:Disulfides; D009566:Nitrates; D009569:Nitric Oxide; D001241:Aspirin