TRPA1 Mediates Aromatase Inhibitor–Evoked Pain by the Aromatase Substrate Androstenedione

Logu, Francesco De; Tonello, Raquel; Materazzi, Serena; Nassini, Romina; Fusi, Camilla; Coppi, Elisabetta; Puma, Simone Li; Marone, Ilaria M.; Sadofsky, Laura R.; Morice, Alyn H.; Susini, Tommaso; Terreni, Alessandro; Moneti, Gloriano; Tommaso, Mariarosaria Di; Geppetti, Pierangelo; Benemei, Silvia

doi:10.1158/0008-5472.can-16-1492

Cited by 20 publications

(24 citation statements)

References 47 publications

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“…20 Notably, the synergistic action of clinically relevant concentrations of letrozole, androstenedione and ROS reproduced inflammatory and neuropathic pain in mice, similar to the musculoskeletal symptoms reported by breast cancer patients treated with aromatase inhibitors. 20 Cancer remarkably disrupts tissue architecture and alters the biochemistry and metabolism of the microenvironment. 21 Oxidative stress generation in cancer cells, 22 as well as in the cells surrounding the tumor, 8,23,24 is one of the most common and major changes associated with cancer growth.…”

Section: Introductionmentioning

confidence: 70%

“…Furthermore, TRPA1 activation by two channel agonists, the aromatase inhibitors, letrozole and the aromatase substrate, androstenedione, was exaggerated by ROS . Notably, the synergistic action of clinically relevant concentrations of letrozole, androstenedione and ROS reproduced inflammatory and neuropathic pain in mice, similar to the musculoskeletal symptoms reported by breast cancer patients treated with aromatase inhibitors …”

Section: Introductionmentioning

confidence: 72%

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Transient receptor potential ankyrin 1 (TRPA1) plays a critical role in a mouse model of cancer pain

Antoniazzi

Nassini

Rigo

et al. 2018

Intl Journal of Cancer

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There is a major, unmet need for the treatment of cancer pain, and new targets and medicines are required. The transient receptor potential ankyrin 1 (TRPA1), a cation channel expressed by nociceptors, is activated by oxidizing substances to mediate pain‐like responses in models of inflammatory and neuropathic pain. As cancer is known to increase oxidative stress, the role of TRPA1 was evaluated in a mouse model of cancer pain. Fourteen days after injection of B16‐F10 murine melanoma cells into the plantar region of the right hind paw, C57BL/6 mice exhibited mechanical and thermal allodynia and thigmotaxis behavior. While heat allodynia was partially reduced in TRP vanilloid 1 (TRPV1)‐deficient mice, thigmotaxis behavior and mechanical and cold allodynia were absent in TRPA1‐deficient mice. Deletion of TRPA1 or TRPV1 did not affect cancer growth. Intrathecal TRPA1 antisense oligonucleotides and two different TRPA1 antagonists (HC‐030031 or A967079) transiently attenuated thigmotaxis behavior and mechanical and cold allodynia. A TRPV1 antagonist (capsazepine) attenuated solely heat allodynia. NADPH oxidase activity and hydrogen peroxide levels were increased in hind paw skin 14 days after c ancer cell inoculation . The antioxidant, α‐lipoic acid, attenuated mechanical and cold allodynia and thigmotaxis behavior, but not heat allodynia. Whereas TRPV1, via an oxidative stress‐independent pathway, contributes partially to heat hypersensitivity, oxidative stress‐dependent activation of TRPA1 plays a key role in mediating thigmotaxis behavior and mechanical and cold allodynia in a cancer pain model. TRPA1 antagonists might be beneficial in the treatment of cancer pain.

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Section: Introductionmentioning

confidence: 70%

Section: Introductionmentioning

confidence: 72%

Transient receptor potential ankyrin 1 (TRPA1) plays a critical role in a mouse model of cancer pain

Antoniazzi

Nassini

Rigo

et al. 2018

Intl Journal of Cancer

Self Cite

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“…Contrary to the above, a positive role in TRPV1 activation by androstenedione has been recently reported. In this sense it was demonstrated that androstenedione activates currents in DRG neurons from the TRPA1 knockout mice and that these currents were inhibited by capsazepine [77], a TRPV1 antagonist, suggesting that these currents were due to TRPV1 activation, Table 1. It is interesting to note that some compounds used as treatments for breast cancer are based on their anti-estrogenic effects using compounds with similar structures to androstenedione and that they cause pain [78].…”

Section: Trpv1 Is Also Targeted By Androgensmentioning

confidence: 99%

“…Thus, a possible synergic effect between androstenedione and the aromatase inhibitors to produce pain was investigated. Whole-cell electrophysiological experiments carried out in HEK293 cells expressing the human TRPA1 channel showed that the application of androstenedione elicited inward currents, which were abolished by a selective TRPA1 blocker [77], Table 1. It was also assayed in mouse DRG neurons, where androstenedione produced calcium influx partially dependent on TRPA1 since DRG neurons from TRPA1 knockout mice displayed residual currents which were abrogated by capsazepine, as was mentioned above [77].…”

Section: Trpa1: Estrogens and Androgens Regulate Its Expression And Fmentioning

confidence: 99%

Steroids and TRP Channels: A Close Relationship

Méndez-Reséndiz

Enciso-Pablo

González‐Ramírez

et al. 2020

IJMS

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Transient receptor potential (TRP) channels are remarkable transmembrane protein complexes that are essential for the physiology of the tissues in which they are expressed. They function as non-selective cation channels allowing for the signal transduction of several chemical, physical and thermal stimuli and modifying cell function. These channels play pivotal roles in the nervous and reproductive systems, kidney, pancreas, lung, bone, intestine, among others. TRP channels are finely modulated by different mechanisms: regulation of their function and/or by control of their expression or cellular/subcellular localization. These mechanisms are subject to being affected by several endogenously-produced compounds, some of which are of a lipidic nature such as steroids. Fascinatingly, steroids and TRP channels closely interplay to modulate several physiological events. Certain TRP channels are affected by the typical genomic long-term effects of steroids but others are also targets for non-genomic actions of some steroids that act as direct ligands of these receptors, as will be reviewed here.

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“…13,21,22 Different from some chemotherapeutic agents that do not appear to directly stimulate TRPA1, 13,21,22 we showed that dacarbazine selectively activates TRPA1 when evaluated in human TRPA1-HEK293 cells and cultured mouse DRG neurons, a response abolished by TRPA1 antagonist HC-030031. The dacarbazine action is like that observed for aromatase inhibitors, exemestane, letrozole and anastrozole; and the aromatase substrate androstenedione, 35,36 which were able to directly activate the TRPA1 causing pain conditions. This evidence is derived from the observation that dacarbazine evoked calcium response in hTRPA1-HEK293 cells but not in naive cells, in which it was abolished by the selective TRPA1 antagonist HC-030031.…”

Section: Discussionmentioning

confidence: 74%

Dacarbazine alone or associated with melanoma‐bearing cancer pain model induces painful hypersensitivity by TRPA1 activation in mice

Brusco

Puma

Chiepe

et al. 2019

Intl Journal of Cancer

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Antineoplastic therapy has been associated with pain syndrome development characterized by acute and chronic pain. The chemotherapeutic agent dacarbazine, used mainly to treat metastatic melanoma, is reported to cause painful symptoms, compromising patient quality of life. Evidence has proposed that transient receptor potential ankyrin 1 (TRPA1) plays a critical role in chemotherapy‐induced pain syndrome. Here, we investigated whether dacarbazine causes painful hypersensitivity in naive or melanoma‐bearing mice and the involvement of TRPA1 in these models. Mouse 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. Mechanical and cold allodynia were evaluated after acute or repeated dacarbazine administration in naive mice or after inoculation of B16‐F10 melanoma cells in C57BL/6 mice. TRPA1 involvement was investigated by using pharmacological and genetic tools (selective antagonist or antisense oligonucleotide treatment and Trpa1 knockout mice). Dacarbazine directly activated TRPA1 in hTRPA1‐HEK293 cells and mouse DRG neurons and appears to sensitize TRPA1 indirectly by generating oxidative stress products. Moreover, dacarbazine caused mechanical and cold allodynia in naive but not Trpa1 knockout mice. Also, dacarbazine‐induced nociception was reduced by the pharmacological TRPA1 blockade (antagonism), antioxidants, and by ablation of TRPA1 expression. TRPA1 pharmacological blockade also reduced dacarbazine‐induced nociception in a tumor‐associated pain model. Thus, dacarbazine causes nociception by TRPA1 activation, indicating that this receptor may represent a pharmacological target for treating chemotherapy‐induced pain syndrome in cancer patients submitted to antineoplastic treatment with dacarbazine.

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TRPA1 Mediates Aromatase Inhibitor–Evoked Pain by the Aromatase Substrate Androstenedione

Cited by 20 publications

References 47 publications

Transient receptor potential ankyrin 1 (TRPA1) plays a critical role in a mouse model of cancer pain

Transient receptor potential ankyrin 1 (TRPA1) plays a critical role in a mouse model of cancer pain

Steroids and TRP Channels: A Close Relationship

Dacarbazine alone or associated with melanoma‐bearing cancer pain model induces painful hypersensitivity by TRPA1 activation in mice

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