Abstract B34: NOSH-aspirin (NBS-1120) a dual nitric oxide and hydrogen sulfide releasing hybrid for treatment of cancer
Authors: Chattopadhyay Mitali , Kodela Ravinder , Lee Diana H. , Le Thuy-Tien C. , Kashfi Khosrow 
Published: January 2014

Introduction: Regular uses of non-steroidal anti-inflammatory drugs (NSAIDs) in general and aspirin in particular have been associated with reductions in a number of cancers including, colon, breast, pancreas and others. However, NSAIDs have significant side effects, which precludes their wide spread use. In our search for a “better 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, is essentially devoid of any cyto-toxicity as judged by lactate dehydrogenase (LDH) release. Here we report our results on the effects of NOSH-aspirin treatment on established tumors in a xenograft model of human colon, breast (both ER- and ER+), and pancreatic cancer cells.

Methods: Compound: NOSH-aspirin was synthesized and purified by us with 1H-NMR verification. Cell lines: Colon, HT-29, HCT 15, and SW 480; breast, MCF-7 (ER+), MDA-MB-231 (ER-, PR-, which does not over express Her2), and HMEpC, normal human mammary epithelial; pancreas, MIA PaCa2 and BxPC3. Xenografts: Male athymic nude (NU/NU) mice (N=10 per cell line) were implanted s.c. in the right flank with HT-29, MCF-7, MDA-MB-231, MIA PaCa2 cells (2 x 106) suspended in 50% Matrigel, after 10 days the animals from each implanted cell line were randomly divided into 2 groups (N = 5/group) and gavaged daily with NOSH-aspirin (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's IC50 in nM at 24h for cell growth inhibition were HT-29 (50 ± 2), HCT 15 (52 ± 3), SW480 (55 ± 5), MCF-7 (250 ± 10), MDA-MB-231 (95 ± 7), HMEpC (20,000 ± 3,000), MIAPaCa2 (52 ± 4), and BxPC3 (62 ± 5). Aspirin's IC50 in all cell lines was greater than 5,000,000 nM at 24h. In all 4 xenografts, NOSH-aspirin had no effect on the weight of the mice and there were no overt signs of toxicity. Tumor volume was reduced as a function of treatment time in all 4 xenografts. Interestingly, the growth rate of ER(−) xenografts was significantly greater than that of ER(+) ones and NOSH-aspirin had a greater effect on the ER(−) vs ER(+) xenografts. Tumor mass for each group were, colon: 2.8 ± 0.51g in untreated and 0.32 ± 0.067g in treated (89% reduction, P=0.005); breast, ER(+): 0.46 ± 0.056g untreated and 0.21 ± 0.035g treated, (55% reduction, P=0.022), ER(−): 1.2 ± 0.33g untreated and 0.11 ± 0.058g treated (91% reduction, P=0.006); pancreas: 2.47 ± 0.24g untreated and 0.62 ± 0.25g treated, (75% reduction, P=0.0031). NOSH-aspirin inhibited growth of these cancer cell xenografts as a result of reduced proliferation (decreased PCNA expression), and induction apoptosis (increased number of TUNEL positive cells). NF-κB, activated in untreated xenografts was significantly inhibited by NOSH-aspirin.

Conclusions: NOSH-aspirin preferentially affects cancer cells and has potent anti-cancer properties. It targets parameters important in determining cellular mass, and inflammation.

Citation Format: Mitali Chattopadhyay, Ravinder Kodela, Diana H. Lee, Thuy-Tien C. Le, Khosrow Kashfi. NOSH-aspirin (NBS-1120), a dual nitric oxide and hydrogen sulfide-releasing hybrid for treatment of cancer. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr B34.