Abstract 2523: Synthetic triterpenoids protect against toxicity and enhance the efficacy of treatment with carboplatin/paclitaxel in experimental lung cancer
Authors: Liby Karen T. , Royce Darlene B. , Risingsong Renee , Williams Charlotte R. , Sporn Michael B. 
Published: June 2012

Abstract
Lung cancer remains the leading cause of cancer deaths worldwide, with no real improvement in 5 yr survival rates in over 30 yrs. While prevention offers the most promising approach for reducing mortality, new drugs are clearly needed. We have previously shown that synthetic triterpenoids, including the methyl ester (Me) and ethyl amide (EA) of CDDO (2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid), are effective for prevention and treatment of experimental lung cancer; CDDO-Me is currently in early clinical trials. When used for treatment of lung cancer in A/J mice, the triterpenoids caused growth-arrest rather than tumor regression, so we tested the triterpenoids in combination with carboplatin and paclitaxel, standard chemotherapeutic agents used to treat human lung cancer. Female A/J mice were injected i.p. with vinyl carbamate to induce lung cancer; adenocarcinomas are visible on lung sections as early as 4 wks after initiation. In a pilot study, mice were fed triterpenoids and received 5 injections of carboplatin (50 mg/kg) and paclitaxel (15 mg/kg), one wk apart, beginning eight wks after initiation. This protocol was toxic in the mice treated with carboplatin/paclitaxel alone, as only 38% (3 of 8) mice survived. In contrast, 88% (14 of 16) of the mice survived when treated with triterpenoids in combination with carboplatin/ paclitaxel. In a second study, lung cancer was induced by vinyl carbamate, but treatment was delayed until 12 wks after initiation, and the 5 carboplatin/ paclitaxel injections were given every other wk instead of every wk. Survival improved to 91% in the carboplatin/paclitaxel group (21 of 23 mice) and was 97% (31 of 32 mice) in the groups given triterpenoid in combination with carboplatin/paclitaxel. Although treatment with carboplatin/paclitaxel alone significantly (P &lt; 0.05) reduced total tumor volume by 81% compared to the control group (16.1 mm3 for the controls vs. 3.1 mm3 for the group treated with carboplatin/paclitaxel), treatment with the combination of CDDO-EA (800 mg/kg diet) and carboplatin/paclitaxel reduced tumor volume to 1.1 mm3, a 93% reduction compared to the controls (P &lt; 0.05 vs. control and carboplatin/paclitaxel alone). In VC1 lung cancer cells derived from a tumor from an A/J mouse, CDDO-EA directly interacted with IKK and cyclin D1, blocked the degradation of IKBα in cells treated with TNFα, decreased inhibited proliferation by decreasing cyclin D1 levels and increasing p21, and induced apoptosis. Ongoing studies will determine whether the combination of CDDO-EA and carboplatin/paclitaxel induces apoptosis in these tumors in vivo and will explore the mechanisms of action for the protection of the triterpenoids against carboplatin/paclitaxel toxicity in normal tissues while simultaneously enhancing the therapeutic effect in lung cancer. Supported by NIH grant R01 CA78814 and Reata Pharmaceuticals, Inc.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2523. doi:10.1158/1538-7445.AM2011-2523