P27 Inhibits Tumor Growth and Induces Mitochondrial Dysfunction in OSCC

Objectives: Oral squamous cell carcinoma (OSCC) is a deadly disease whose incidence and mortality rates are ever-increasing due to lack of efficacious therapies. We discovered that Vanilloids (Transient Receptor Potential Vanilloid Subtype 1 (TRPV1) agonists) have anti-tumor effects against OSCC in vivo. The natural compound, Polygodial, is also a TRPV1 agonist and thus was tested against OSCC in vitro and in vivo. We demonstrated significant anti-tumor effects of Polygodial in vivo; however a strong, yet transitory, inflammation occurred. We then developed several Polygodial analogs with the goal of generating more potent compounds that do not elicit inflammation. Objective: To evaluate Polygodial analogs’ anti-proliferative effects in vitro and in vivo and to assess their mechanism(s)-of-action.
Methods: Methods: MTS assays were performed in the OSCC cell line, Cal27. Cal27-derived xenografts were used to evaluate anti-tumor effects in nude mice. Tumor-bearing mice were treated by intra-tumor injections (40μg) every other day for two weeks with: 1) vehicle, 2) Polygodial, 3) P3, or 4) P27. Mitochondrial depolarization studies were performed to determine effects on mitochondrial function.
Results: Results: Polygodial, P3, and P27 significantly reduced OSCC viability in vitro (IC₅₀ ~ 10μM). Similar to our previous findings, Polygodial significantly reduced tumor growth by day 12 (p<0.01) but induced a dramatic inflammatory response from day 2 through day 6. P3 was minimally effective in vivo (p <0.05 day 22). However, P27 had significant anti-tumor effects (p<0.001) that were equivalent to Polygodial with no adverse inflammatory response. Mitochondrial function studies confirmed a dose-dependent depolarization of the mitochondria and apoptosis in response to P27.
Conclusions: Conclusion: Polygodial and P27 have significant anti-tumor activity in OSCC. P27 mediates mitochondrial function with no inflammatory response; therefore P27 is a novel therapeutic agent with potential to treat OSCC without adverse side effects. Calcium imaging studies are underway to determine if P27 interacts with TRPV1 (agonist/antagonist).