Abstract
Abstract Introduction: In our search for a better non-steroidal anti-inflammatory drug (NSAID) we have synthesized a series of nitric oxide-, and hydrogen sulfide-releasing hybrid compounds that have IC50s for cell growth inhibition in the low nano-molar range. We have termed these NOSH compounds. Our lead agent, NOSH-aspirin is in the order of 100,000 to 250,000-fold more potent than aspirin in inhibiting colon cancer cell growth over a 24-72h time period. NOSH-aspirin although highly potent, has very limited cyto-toxicity, lactate dehydrogenase (LDH) release at 4 times its IC50 for cell growth inhibition was less than 10% at 24h. Here we report our results on the effects of NOSH-aspirin treatment on established tumors in a xenograft model of human colon cancer cells. Methods: Compound: NOSH-aspirin was synthesized and purified by us with 1H-NMR verification. Cell line: HT-29 human adenocarcimoma; Xenografts: Male athymic SKID mice were implanted s.c. in the right flank with HT-29 (2 x 106) cells suspended in 50% Matrigel, after 10 days the animals were randomly divided into 4 groups (N = 7/group) and gavaged daily with NOSH-aspirin (25 or 50 or 100 mg/kg body weight) or vehicle. Tumor volume and animal weight were recorded every 3 days. After 3 weeks of treatment, mice were sacrificed, tumors excised, weighed, and fixed in 10% buffered formalin for immunohistochemical studies. Results: NOSH-aspirin had no effect on the weight of the mice even at the highest concentration used. There were no overt signs of toxicity. It dose-dependently reduced tumor mass by 50 ± 7%, 75 ± 5%, 90 ± 3 % at 25, 50, and 100 mg/kg, respectively. Tumor volume was also dose-dependently reduced as a function of time. NOSH-aspirin inhibited growth of HT-29 colon cancer cells xenografts as a result of reduced proliferation (decreased PCNA expression), and induction apoptosis (increased number of TUNEL positive cells). NF-κB, activated in control xenografts was significantly inhibited by NOSH-aspirin. Conclusions: NOSH-aspirin has potent anti-cancer affects and merits further evaluation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3898. doi:1538-7445.AM2012-3898
Published Version
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call