capsazepine and Carcinoma--Squamous-Cell

Oral squamous cell carcinoma (OSCC) is a deadly disease with a mere 40% five-year survival rate for patients with advanced disease. Previously, we discovered that capsazepine (CPZ), a transient receptor potential channel, Vanilloid subtype 1 (TRPV1) antagonist, has significant anti-tumor effects against OSCC via a unique mechanism-of-action that is independent of TRPV1. Thus, we developed novel CPZ analogs with more potent anti-proliferative effects (CIDD-24, CIDD-99, and CIDD-111).. Using OSCC xenograft models, we determined the efficacy of these analogs in vivo. TRPV1 interactions were evaluated using calcium imaging and a rat model of orofacial pain. Anti-cancer mechanism(s)-of-action were assessed by cell cycle analysis and mitochondrial depolarization assays.. CIDD-99 was the most potent analog demonstrating significant anti-tumor effects in vivo (P < 0.001). CIDD-24 was equipotent to the parent compound CPZ, but less potent than CIDD-99. CIDD-111 was the least efficacious analog. Calcium imaging studies confirmed that CIDD-99 neither activates nor inhibits TRPV1 confirming that TRPV1 activity is not involved in its anti-cancer effects. All analogs induced an S-phase block, dose-dependent mitochondrial depolarization, and apoptosis. Histological analyses revealed increased apoptosis and reduced cell proliferation in tumors treated with these analogs. Importantly, CIDD-99 had the most dramatic anti-tumor effects with 85% of tumors resolving leaving only minute traces of viable tissue. Additionally, CIDD-99 was non-noxious and demonstrated no observable adverse reactions CONCLUSION: This study describes a novel, highly efficacious, CPZ analog, CIDD-99, with dramatic anti-tumor effects against OSCC that may be efficacious as a lone therapy or in combination with standard therapies.

Topics: Animals; Apoptosis; Capsaicin; Carcinoma, Squamous Cell; Cell Line, Tumor; Endoplasmic Reticulum Stress; Female; Humans; Isoquinolines; Male; Mice; Mice, Nude; Mitochondria; Mouth Neoplasms; Rats; Rats, Sprague-Dawley; TRPV Cation Channels; Xenograft Model Antitumor Assays

To investigate the mechanisms underlying cancer pain, we developed a rat model of cancer pain by inoculating SCC-158 into the rat hind paw, resulting in squamous cell carcinoma, and determined the time course of thermal, mechanical sensitivity, and spontaneous nocifensive behavior in this model. In addition, pharmacological and immunohistochemical studies were performed to examine the role played by transient receptor potential vanilloid (TRPV)1 and TRPV2 expressed in the dorsal root ganglia. Inoculation of SCC-158 induced marked mechanical allodynia, thermal hyperalgesia, and signs of spontaneous nocifensive behavior, which were diminished by systemic morphine administration. Intraplantar administration of the TRPV1 antagonist capsazepine or TRP channels antagonist ruthenium red did not inhibit spontaneous nocifensive behavior at all. However, intraplantar administration of capsazepine or ruthenium red completely inhibited mechanical allodynia and thermal hyperalgesia produced by SCC-158 inoculation. Immunohistochemically, the number of TRPV1-positive, large-sized neurons increased, whereas there was no change in small-sized neurons in the dorsal root ganglia. Our results suggest that TRPV1 play an important role in the mechanical allodynia and thermal hyperalgesia caused by SCC-158 inoculation.. We describe a cancer pain model that induced marked mechanical allodynia, thermal hyperalgesia, signs of spontaneous nocifensive behavior, and upregulation of TRPV1. Mechanical allodynia and thermal hyperalgesia were inhibited by TRP channel antagonists. The results suggest that TRPV1 plays an important role in the model of cancer pain.

Topics: Analgesics, Opioid; Animals; Behavior, Animal; Capsaicin; Carcinoma, Squamous Cell; Cell Line, Tumor; Foot Diseases; Ganglia, Spinal; Hyperalgesia; Immunohistochemistry; Injections, Intraperitoneal; Injections, Subcutaneous; Male; Morphine; Neoplasms, Experimental; Nociceptors; Pain; Pain Measurement; Pain Threshold; Rats; Rats, Inbred F344; Ruthenium Red; TRPV Cation Channels