capsazepine and Neoplasms

We previously demonstrated that capsazepine (CPZ), a synthetic transient receptor potential Vanilloid subtype 1 (TRPV1) antagonist, has significant anti-cancer effects in vivo. The purpose of this study was to develop more potent analogs based upon CPZ pharmacophore and structure-activity relationships (SAR) across analogs. We generated 30 novel compounds and screened for their anti-proliferative effects in cultured HeLa cervical cancer cells. Cell viability assays identified multiple compounds with IC

Topics: Animals; Antineoplastic Agents; Capsaicin; Cell Line, Tumor; Cell Proliferation; Female; Humans; Mice, Nude; Molecular Structure; Neoplasms; Structure-Activity Relationship; TRPV Cation Channels; Xenograft Model Antitumor Assays

Radiosensitizers are used in cancer therapy to increase the γ-irradiation susceptibility of cancer cells, including radioresistant hypoxic cancer cells within solid tumors, so that radiotherapy can be applied at doses sufficiently low to minimize damage to adjacent normal tissues. Radiation-induced DNA damage is repaired by multiple repair systems, and therefore these systems are potential targets for radiosensitizers. We recently reported that the transient receptor potential vanilloid type 1 (TRPV1) channel is involved in early responses to DNA damage after γ-irradiation of human lung adenocarcinoma A549 cells. Therefore, we hypothesized that TRPV1 channel inhibitors would have a radiosensitizing effect by blocking repair of radiation-induced cell damage. Here, we show that pretreatment of A549 cells with the TRPV1 channel inhibitors capsazepine, AMG9810, SB366791 and BCTC suppressed the γ-ray-induced activation of early DNA damage responses, i.e., activation of the protein kinase ataxia-telangiectasia mutated (ATM) and accumulation of p53-binding protein 1 (53BP1). Further, the decrease of survival fraction at one week after γ-irradiation (2.0 Gy) was enhanced by pretreatment of cells with these inhibitors. On the other hand, inhibitor pretreatment did not affect cell viability, the number of apoptotic or necrotic cells, or DNA synthesis at 24 h after irradiation. These results suggest that inhibition of DNA repair by TRPV1 channel inhibitors in irradiated A549 cells caused gradual loss of proliferative ability, rather than acute facilitation of apoptosis or necrosis. TRPV1 channel inhibitors could be novel candidates for radiosensitizers to improve the efficacy of radiation therapy, either alone or in combination with other types of radiosensitizers.

Topics: Acrylamides; Anilides; Animals; Apoptosis; Bridged Bicyclo Compounds, Heterocyclic; Capsaicin; Cell Line, Tumor; Cell Survival; Cinnamates; DNA Damage; Gamma Rays; Humans; Mice; Necrosis; Neoplasms; Pyrazines; Pyridines; Radiation-Sensitizing Agents; TRPV Cation Channels

The identification of self-renewing and multipotent neural stem cells (NSCs) in the mammalian brain holds promise for the treatment of neurological diseases and has yielded new insight into brain cancer. However, the complete repertoire of signaling pathways that governs the proliferation and self-renewal of NSCs, which we refer to as the 'ground state', remains largely uncharacterized. Although the candidate gene approach has uncovered vital pathways in NSC biology, so far only a few highly studied pathways have been investigated. Based on the intimate relationship between NSC self-renewal and neurosphere proliferation, we undertook a chemical genetic screen for inhibitors of neurosphere proliferation in order to probe the operational circuitry of the NSC. The screen recovered small molecules known to affect neurotransmission pathways previously thought to operate primarily in the mature central nervous system; these compounds also had potent inhibitory effects on cultures enriched for brain cancer stem cells. These results suggest that clinically approved neuromodulators may remodel the mature central nervous system and find application in the treatment of brain cancer.

Topics: Animals; Cell Survival; Cells, Cultured; Mice; Molecular Structure; Neoplasms; Neurons; Pharmaceutical Preparations; Sensitivity and Specificity; Stem Cells

We developed a mouse model of cancer pain to investigate its underlying mechanisms. SCC-7, squamous cell carcinoma (SCC) derived from C3H mice, was inoculated subcutaneously into either the plantar region or thigh in male C3H/Hej mice. Heat and mechanical sensitivity as well as spontaneous behavior were measured at the plantar surface of the ipsilateral hind paw after the inoculation. Inoculated sites were histologically examined, and the expression of capsaicin receptors (TRPV1) was examined in the dorsal root ganglia (DRG) to clarify their potential contribution to pain sensitivity. Inoculation of cancer cells induced marked heat hyperalgesia and mechanical allodynia in the ipsilateral hind paw for two weeks in both plantar- and thigh-inoculation models. Signs of spontaneous pain, such as lifting, licking and flinching of the paw were also observed. However, further growth of the tumor reversed the mechanical allodynia in both plantar- and thigh-inoculation models, and heat hyperalgesia in thigh-inoculation models. Histologically, no infiltration of the tumor cells into the nerve was observed. TRPV1 immunoreactive cells increased in the L5 DRG on day 7, but returned to the control level on day 15 post-inoculation. Intraperitoneal administration of the competitive TRPV1 antagonist capsazepine inhibited hyperalgesia induced by tumor cell-inoculation in either plantar- or thigh-inoculated animals. This study indicated that inoculation of SCC resulted in spontaneous pain, heat hyperalgesia and mechanical allodynia. The altered expression of TRPV1 in the DRG may be involved in behavioral changes in this model.

Topics: Animals; Body Temperature; Capsaicin; Cell Count; Cell Line, Tumor; Cell Size; Disease Models, Animal; Dose-Response Relationship, Drug; Ganglia, Spinal; Humans; Hyperalgesia; Immunohistochemistry; Male; Mice; Mice, Inbred C3H; Neoplasm Transplantation; Neoplasms; Pain; Pain Measurement; Pain Threshold; Reaction Time; Staining and Labeling; Time Factors; TRPV Cation Channels