Abstract 2513: NOSH-aspirin alone or in combination with 5-fluorouracil induces tumor regression in a xenograft model of estrogen receptor positive breast cancer

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Introduction: In the US, breast cancer is the second leading cause of cancer deaths in women. Estrogen receptor positive [ER(+)] breast cancers represent 70-75% of human breast cancers. Selective estrogen receptor modulators such as tamoxifen, have a well-established role in preventing ER (+) breast cancer. However, these agents have limitations due to development of tamoxifen resistance. It is now well accepted that non-steroidal anti-inflammatory drugs (NSAIDs) reduce the risk of and mortality from colon cancer and constitute the prototypical colon cancer chemopreventive agents. Recent exhaustive meta-analysis also provides evidence that NSAID also reduce the risk for ER(+) breast cancer. However, regular NSAID use may lead to life threatening side effects. To overcome these limitations, we developed NOSH-aspirin, a nitric oxide-, and hydrogen sulfide-releasing hybrid that is very potent yet devoid of any cyto-toxicity. Here we report on the effects of NOSH-aspirin alone or in combination with 5-fluorouracil (5-FU) on treatment of established tumors in a xenograft model of human ER(+) breast cancer. Methods: NOSH-aspirin was synthesized and purified by us. Cell line: breast MCF-7 (ER+), Xenografts: Female athymic nude mice (N=25) were implanted s.c. in the right flank with MCF-7 cells (2 x 106), when the tumor volumes reached ∼100 mm3, the animals were randomly divided into 5 groups (N=5/gp) and treated with NOSH-aspirin (po,50 and 100 mg/kg body wt/day), 5-FU (ip, 10 mg/kg x 2/week), high dose NOSH-aspirin+5-FU as above, or vehicle (po). 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 IHC studies. We also weighed the livers and the kidneys. Results: NOSH-aspirin dose-dependently reduced tumor volume as a function of time. 5-FU also significantly reduced tumor volume, however, there was a synergistic effect in the combination group. Tumor mass at sacrifice in each group was, vehicle (2.35±0.22g), NOSH-aspirin 50 mg/kg (0.80±0.28g, 66% reduction, P<0.01), NOSH-aspirin 100 mg/kg (0.17±0.08g, 93% reduction, P<0.001), 5-FU (0.065±0.024g, 97% reduction, P<0.001), high dose NOSH-aspirin+5-FU (0.018±0.007g 99% reduction P<0.001). The tumor regression was significantly more in the combination group compared to NOSH-aspirin or 5-FU alone. NOSH-aspirin had no effect on the weight of the mice whether alone or in combination with 5-FU, there were no overt signs of toxicity. There was a 10% reduction in the weight of animals in the 5-FU group; however, this difference was not significant. There were no differences in liver or kidney masses amongst the groups. Conclusions: NOSH-aspirin has potent anti-cancer properties and demonstrates synergistic properties with 5-FU. It merits further evaluation as a chemotherapeutic agent. Citation Format: Sarin A. Soyemi, Mitali Chattopadhyay, Khosrow Kashfi. NOSH-aspirin alone or in combination with 5-fluorouracil induces tumor regression in a xenograft model of estrogen receptor positive breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2513. doi:10.1158/1538-7445.AM2014-2513