H-Ras Inhibition With Fendiline for Oral Squamous Cell Carcinoma Therapy

Objectives: Poor efficacy, chemotoxicity and/or chemoresistance are primary issues associated with the current therapeutics (cisplatin, cetuximab) used for the treatment of oral squamous cell carcinomas (OSCC) and therefore, there is an unmet need for novel chemotherapeutics. H-Ras is commonly mutated in OSCC and is a major target for drug development. Fendiline, an antianginal agent, was previously shown to inhibit oncogenic H-Ras signaling in immortalized cell lines. Goals of this study were (1) to compare the effect of fendiline against farnesyl transferase inhibitor FTI-276 (another H-Ras inhibitor) and U0126 (inhibitor of Ras effector MEK) on signaling, proliferation, clonogenic survival and migration of H-Ras-transformed OSCC cells, and (2) to determine the effect of fendiline in combination treatment with other chemotherapeutic agents on proliferation of OSCC cells.
Methods: Wild type- (UM-SCC-H-RasWT) and oncogenic H-Ras-expressing (UM-SCC-H-RasG12V and HN31) oral cancer cell lines were utilized. Western blot analysis, CyQUANT® cell proliferation assay, clonogenic survival assay and wound scratch assay were utilized to determine the effect of drug treatment on cell signaling, proliferation, ability to form clones and migration, respectively.
Results: Fendiline selectively inhibited H-Ras effectors pERK and pAkt in UM-SCC-H-RasG12V and/or HN31 without having any effect on UM-SCC-H-RasWT cells; however, FTI-276 and U0126 non-selectively decreased pERK in all cell lines. Fendiline, compared to FTI-276 and U0126, was more potent in inhibiting proliferation of UM-SCC-H-RasG12V and HN31 cells with little or no effect on UM-SCC-H-RasWT. Fendiline also significantly inhibited migration of the cells but did not have any statistically significant effects on clonogenic survival. Dose-response studies of chemotherapeutic agents cisplatin or erlotinib with 0 or 10 µM fendiline showed that combination with fendiline was more efficacious in inhibiting proliferation of UM-SCC-H-RasG12V and HN31 cells.
Conclusions: Fendiline has the potential to be used as a therapeutic in mono- and combination therapy for the treatment of OSCC.