Abstract
Chemoresistant cancer cells express high levels of aldehyde dehydrogenases (ALDHs), particularly in head and neck squamous cell carcinoma (HNSCC). The ALDH family of enzymes detoxify both exogenous and endogenous aldehydes. Since many chemotherapeutic agents, such as cisplatin, result in the generation of cytotoxic aldehydes and oxidative stress, we hypothesized that cells expressing high levels of ALDH may be more chemoresistant due to their increased detoxifying capacity and that inhibitors of ALDHs may sensitize them to these drugs. Here, we show that overall ALDH activity is increased with cisplatin treatment of HNSCC and that ALDH3A1 protein expression is particularly enriched in cells treated with cisplatin. Activation of ALDH3A1 by a small molecule activator (Alda-89) increased survival of HNSCC cells treated with cisplatin. Conversely, treatment with a novel small molecule ALDH inhibitor (Aldi-6) resulted in a marked decrease in cell viability, and the combination of Aldi-6 and cisplatin resulted in a more pronounced reduction of cell viability and a greater reduction in tumor burden in vivo than what was observed with cisplatin alone. These data indicate that ALDH3A1 contributes to cisplatin resistance in HNSCC and that the targeting of ALDH, specifically, ALDH3A1, appears to be a promising strategy in this disease.
Highlights
About 650,000 new cases of head and neck squamous cell carcinoma (HNSCC) arise each year worldwide, and the 5-year survival rate for advanced non-human papilloma virus (HPV)-associated HNSCC has remained at approximately 50% for the last 20 years [1,2,3]
When another oral cavity squamous cell carcinoma cell line PCI-13 was treated with cisplatin in culture, we observed a 7-fold increase in aldehyde dehydrogenases (ALDHs) activity, in treated cells compared to control
ALDH isozymes are responsible for oxidizing intracellular reactive aldehydes and protecting cells from reactive oxygen species (ROS)-induced oxidative insult [11, 12, 15, 30], but the role of ALDH in the cisplatin chemosensitivity in HNSCC cells has not been investigated in detail
Summary
About 650,000 new cases of HNSCC arise each year worldwide, and the 5-year survival rate for advanced non-human papilloma virus (HPV)-associated HNSCC has remained at approximately 50% for the last 20 years [1,2,3]. Several signaling pathways involved in the development of cisplatin resistance in cancer have been identified. These include increased inactivation by cellular antioxidants and antioxidant enzymes (Glutathione (GSH) and Glutathione S-Transferase (GST)); increased cisplatin efflux by upregulated P-type ATPases; overexpression of multidrug resistance protein (MRP2), a member of ABC membrane transporters that mediate the ATP-dependent cellular efflux of cisplatin; reduced uptake by downregulated plasma membrane copper transporter (CTR1); decreased efficacy by increased expression of cisplatin binding proteins (e.g., voltage dependent anion channel (VDAC)); www.impactjournals.com/oncotarget and upregulation of antiapoptotic members of the Bcl proteins [7,8,9,10]. Due to the heterogeneous nature of resistance to cisplatin, effective ways to sensitize HNSCC to cisplatin have not been developed [9]
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