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Therapeutic Targeting of TRPV1 for the Treatment of Chronic Pain Associated with Prostate Cancer Bone Metastasis
Annual rept. 1 Jul 2011-30 Jun 2012
IOWA STATE UNIV IOWA CITY
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Prostate cancer PCa is the most common cause of cancer in men, with advanced form of this cancer frequently leads to bone metastasis, resulting in moderate to severe chronic pain in the back, pelvis and hips, thereby affecting the survivorship and quality of life in these patients. However, the currently available analgesics do not provide effective pain management under these pathological conditions. We proposed to study the precise cellular and molecular mechanisms that underlie nociceptor sensitization and pain sensation associated with bone-metastasized PCa. Specifically, our study is aimed at determining the role of prostate cancer bone metastasis-specific inflammatory factors, IL-6 and TNF- , PTHrP and ET-1 on upregulation of TRPV1 channel functionexpression, and nociceptor sensitization. Further, to test this hypothesis in vivo, we proposed to determine the role of IL-6TNF- PTHrPET-1 in mediating pain sensitization in scacidice with xenografts of human PCa cells that metastasize to bones. By far our results show that IL-6TNF- PTHrPET-1 sensitize TRPV1 channel activity in sensory neurons that innervate bones. Our results also show that in the presence of IL-6TNF- PTHrPET-1, the TRPV1 channel could be activated at mild acidic pH conditions that are hallmarks of metastatic bone tumor microenvironment. Such modulations and mild acid activation of TRPV1 could lead to constitutive sensory neurons firings thereby provide a mechanism for chronic pain associated with bone-metastasized PCa. Our results on bone-related pain behavior assessments in acid mouse xenografts of human PCa cells, 22Rv1-luc cells, identified several chronic and un-evoked pain behaviors in these mice, specific to bone-metastasized tumor growth.
APPROVED FOR PUBLIC RELEASE