In Vitro Sarcoma Cells Release a Lipophilic Substance That Activates the Pain Transduction System via TRPV1 |
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Authors: | Meeghan A Lautner MD Shivani B Ruparel MS PhD Mayur J Patil MS Kenneth M Hargreaves PhD |
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Institution: | 1. Department of Surgery, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA 2. Department of Endodonitcs, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
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Abstract: | Background Despite success in treating many forms of cancer, pain associated with malignancy remains a serious clinical issue with a poorly understood etiology. This study determined if certain sarcoma cell lines produced a soluble factor that activates the TRPV1 ion channel expressed on nociceptive sensory neurons, thereby activating a major pain transduction system. Materials and Methods Trigeminal ganglia were harvested from rats and cultured. A rhabdomyosarcoma (CRL1598) and osteosarcoma (CRL 1543) cell line were grown to 75% confluency. Conditioned media (CM) was collected after 24 h of exposure and subjected to reverse phase chromatography. Neuronal activation in the presence of CM was measured using iCGRP RIA and calcium imaging after treatment with vehicle or I-RTX, a potent TRPV1 antagonist. Data were analyzed by ANOVA/Bonferroni or t test. Results The rhabdomyosarcoma CM produced a 4-fold increase in iCGRP release compared with control media (P < 0.001). The osteosarcoma cell line CM produced a 7-fold increase in iCGRP release compared with control media (P < 0.001). This evoked iCGRP release was via TRPV1 activation since the effect was blocked by the antagonist I-RTX. The application of rhabdomyosarcoma CM produced about a 4-fold increase in Ca2+]I levels (P < 0.001), and this effect was blocked by pretreatment with the TRPV1 antagonist, I-RTX. Conclusions We have shown that certain sarcoma cell lines produce a soluble, lipophilic factor that activates the peripheral nociceptor transduction system via TRPV1 activation, thereby contributing to cancer pain. Further investigations are needed to develop tumor-specific analgesics that do not produce unwanted or harmful side-effects. |
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