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(PTH14) Dacarbazine alone or associated with melanoma-bearing cancer pain model induces painful hypersensitivity by TRPA1 activation in mice


Authors:

Cássia Silva

Evelyne Da Silva Brum

Camila Camponogara

Caren Tatiane De David Antoniazzi

Francesco De Logu, Dr. – University of Florence

Simone Li Puma, MSc – PhD student, University of Florence

Indiara Brusco

Sara Oliveira

Gabriela Trevisan, PHD – Professor Adjunct, Federal University of Santa Maria

Romina Nassini, PhD

Abstract:

Background and Aims : Antineoplastic therapy has been associated with painful syndrome development characterized by acute and neuropathic pain (1). The chemotherapeutic agent dacarbazine, used mainly to treat metastatic melanoma, is reported to cause painful symptoms, compromising patients’ quality of life (2). Evidence has proposed that transient receptor potential ankyrin 1 (TRPA1) plays a critical role in chemotherapy-induced painful syndrome (1). Here, we investigated whether the dacarbazine causes painful hypersensitivity in naïve or melanoma-bearing mice and the involvement of TRPA1 in these models.


Methods : Mice dorsal root ganglion (DRG) neurons and human TRPA1 transfected HEK293 (hTRPA1-HEK293) cells were used to evaluate the TRPA1-mediated calcium response evoked by dacarbazine (3). Mechanical and cold allodynia were evaluated after acute or repeated dacarbazine administration in naïve mice or after inoculation of B16-F10 melanoma cells in C57BL/6 mice (3). The TRPA1 involvement was investigated using pharmacological and genetic tools (selective antagonist or antisense oligonucleotide treatment and Trpa1 knockout mice) (3).


Results : Dacarbazine directly activated TRPA1 in hTRPA1-HEK293 cells and mice DRG neurons and appears to sensitize TRPA1 indirectly by generating oxidative stress products. Moreover, dacarbazine caused mechanical and cold allodynia in naïve but not in Trpa1 knockout mice, and dacarbazine-induced nociception was reduced by the pharmacological TRPA1 blockade (antagonism), antioxidants, and by ablation of TRPA1 expression. The TRPA1 pharmacological blockade also reduced the dacarbazine-induced nociception in a tumor-associated pain model.

Conclusions : Thus, dacarbazine causes nociception by TRPA1 activation, indicating that this receptor may represent a pharmacological target for treating chemotherapy-induced painful syndrome in cancer’ patients submitted to the antineoplastic treatment with dacarbazine.


References : (1) Nassini R, Materazzi S, Benemei S, Geppetti P. The TRPA1 channel in inflammatory and neuropathic pain and migraine. Rev Physiol Biochem Pharmacol. 2014;167:1–43.
(2) Grob J, Amonkar MM, Martin-Algarra S, Demidov L V., Goodman V, Grotzinger K, et al. Patient perception of the benefit of a BRAF inhibitor in metastatic melanoma: quality-of-life analyses of the BREAK-3 study comparing dabrafenib with dacarbazine. Ann Oncol Off J Eur Soc Med Oncol. 2014;25:1428–36.
(3) Trevisan G, Materazzi S, Fusi C, Altomare A, Aldini G, Lodovici M, et al. Novel therapeutic strategy to prevent chemotherapy-induced persistent sensory neuropathy by TRPA1 blockade. Cancer Res. 2013;73:3120–31.

Conflicts of Interest : No Conflicts of Interest.

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