Abstract 3749: Novel aldehyde dehydrogenase inhibitors as potential anti-chemoresistance drugs for head and neck cancers

Abstract

Abstract The 19 human aldehyde dehydrogenase (ALDH) gene products are enzymes that metabolize a wide range of reactive aldehydes, including those generated by the metabolism of drugs, alcohol, cigarette smoke and organic compounds. These toxic aldehydes are metabolized into respective non-reactive, non-toxic acids. We reasoned that expression of high levels of ALDH support cancer stem cells growth and chemoresistance by detoxifying metabolic aldehydes and aldehydic intermediates of common chemotherapy drugs. Thus, inhibitors of ALDHs (Aldis) may potentiate current treatments. Many malignant cancer cells and cancer stem cells (CSCs) are resistant to chemotherapy, which can lead to secondary relapses. Further, because head and neck cancer (HNC) stem cells express high levels of ALDHs, Aldis may be useful in increasing sensitivity of these tumors to chemotherapy. Testing several different HNC cell lines demonstrated that SCC4 cells are more resistant to cisplatin treatment and PCI13 cells are less resistant (e.g., at 100μM cisplatin, 30±2% of SCC4 cells survived vs. 15±6% of PCI13 cells; n=16). After cisplatin treatment (15μM for 8 days), ALDH activity increased in SCC4 more than in PCI13 (35±5% vs. 2±0.5% increase) as compared with non-treated cells measured. Co-treatment of cisplatin with Aldi-6 reduced ALDH activity in SCC4 by 67% as measured by Aldefluor assay. When cells were treated with Aldi-6 (an ALDH1, 2 and 3 inhibitor) together with cisplatin, Aldi-6 increased cell death by 30% in SCC4 and by 10% in PCI13 compared with cells treated with cisplatin alone (n=8 each). ALDH3A1 protein levels (but not ALDH1 or 2) increased with cisplatin treatment by ∼100 fold and 25 fold, respectively, in SCC4 and PCI13 as compared with non-treated cells measured by Western blot. Based on this data, we tested the efficacy of Aldi-6 in vivo. Tumor (SCC4)-bearing mice were divided into 4 groups and were treated for two weeks with vehicle, Aldi-6 (8mg/kg/day, delivered via an osmotic pump), cisplatin (2mg/kg/BW, ip injection, 2/week) or cisplatin+Aldi-6. Aldi-6 alone resulted in smaller tumors (average tumor volume (mm3): vehicle, 2,945±112; Aldi6, 773±481). Aldi-6 also enhanced cisplatin reduction of tumor size by more than 60% as compared with cisplatin treatment alone (average tumor volume (mm3): cisplatin, 1,560; Aldi6+cisplatin, 597±112; n=3-6). In conclusion, we found that increased ALDH3A1 levels in HNCs following cisplatin treatment in culture and in vivo may contribute to tumor growth and therefore, ALDH3A1 inhibitors may be suitable as chemotherapeutic agents alone; ALDH3A1 inhibitors may also reduce chemoresistance to cisplatin. Understanding the role of ALDH in HNC not only provides insight into the chemoresistance of this disease, but it may also provide novel strategies for therapy. Citation Format: Jeewon Kim, JuneHo Shin, Che-Hong Chen, Leslie Cruz, Lovisa Farnebo, Jieying Yang, John B. Sunwoo, Daria Mochly-Rosen. Novel aldehyde dehydrogenase inhibitors as potential anti-chemoresistance drugs for head and neck cancers. [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 3749. doi:10.1158/1538-7445.AM2014-3749