Paclitaxel Regulates TRPA1 Function and Expression Through PKA and PKC.

Paclitaxel (PTX) is a frequently used anticancer drug that causes peripheral neuropathy. Transient receptor potential ankyrin 1 (TRPA1), a plasma membrane calcium channel, has been associated with PTX toxicity and with other chemotherapy agents such as oxaliplatin and vincristine. However, the effect of PTX on the functional expression and calcium currents of TRPA1 has not been determined. The present study shows the effect of PTX on TRPA1 activity in a neuronal cell line (SH-SY5Y). The effect of PTX on the expression of TRPA1 was assessed through quantitative PCR and Western blot analyses to determine the relative mRNA and protein expression levels. To assess the effect on calcium flux and currents, cells were exposed to PTX; simultaneously, a specific agonist and antagonist of TRPA1 were added to evaluate the differential response in exposed versus control cells. To assess the effect of PKA, PKC and PI3K on PTX-induced TRPA1 increased activity, selective inhibitors were added to these previous experiments. PTX increased the mRNA and protein expression of TRPA1 as well as the TRPA1-mediated Ca2+ currents and intracellular Ca2+ concentrations. This effect was dependent on AITC (a selective specific agonist) and was abolished with HC-030031 (a selective specific antagonist). The inhibition of PKA and PKC reduced the effect of PTX on the functional expression of TRPA1, whereas the inhibition of PI3K had no effects. PTX-induced neuropathy involves TRPA1 activity through an increase in functional expression and is regulated by PKA and PKC signaling. These findings support the role of the TRPA1 channel in the mechanisms altered by PTX, which can be involved in the process that lead to chemotherapy-induced neuropathy.

Neuropatia periférica induzida por quimioterápicos: sintomas e o risco de queda em mulheres idosas com câncer / Peripheral neuropathy induced by chemotherapy: symptoms and the risk of falling in elderly women with cancer

Introdução: Os avanços nas áreas da saúde e tecnologia favoreceram o processo de transição demográfica e o aumento da expectativa de vida. Consequentemente, o aumento da população idosa ocasiona um aumento das doenças crônicas não-transmissíveis, que incluem o câncer, considerado a segunda principal causa de morte em todo mundo. Dentre as diversas opções de tratamento do câncer destaca-se a quimioterapia, que durante seu uso o paciente pode apresentar diferentes eventos adversos. Um destes eventos é a neurotoxicidade, conhecida como neuropatia periférica induzida por quimioterápicos (NPIQ), que é caracterizada como uma lesão inflamatória ou degenerativa dos nervos periféricos. Manifesta-se por sintomas sensoriais típicos, como perda de sensibilidade nos membros e perda de reflexos, fraqueza em mãos e pés e disestesias, perda de discriminação entre o toque e temperatura (frio e calor), cujas manifestações clínicas incluem dor, formigamento, choque e queimação, e podem implicar em consequências negativas para a vida cotidiana e tornando-se mais vulnerável a ocorrências de quedas. Objetivos: Avaliar a ocorrência da NPIQ e o risco de queda em mulheres idosas com diagnóstico de câncer. Métodos: Estudo quantitativo, descritivo e transversal, desenvolvido com 60 mulheres idosas que realizavam o tratamento quimioterápico para qualquer tipo de câncer. Os dados coletados foram sócio-demográficos e sobre o câncer, e foram aplicados os instrumentos: Escala de Risco de Queda (Fall Risk Score), Escala de Fragilidade de Edmonton (Edmonton Frail Scale) e Ferramenta de Avaliação de Neuropatia Periférica Induzida por Quimioterapia (FANPIQ). Os dados foram digitados no Microsoft Excel, e analisado no Statistical Package for the Social Sciences - SPSS v. 22.0. Foram realizadas análises descritivas com média e desvio padrão, analítica e testes de regressão multivariada. Resultados: A média de idade das participantes foi 69,57 (DP±7,63) anos, 58,3% apresentava hipertensão arterial e 30% diabetes mellitus, 96,7% utilizavam algum tipo de medicação e 75% apresentavam câncer de mama. Quanto ao risco de queda, 36,7% das participantes afirmaram já ter apresentado algum tipo de queda nos últimos 12 meses, com ou sem lesão; entretanto somente 6,7% apresentaram algum déficit sensorial. Na avaliação da fragilidade, 58,3% das idosas não precisavam de auxílio para realizar atividades básicas da vida diária, e 48,3% das participantes foram aprovadas na cognição. Quanto aos sintomas neuropáticos que avaliou a ocorrência de dormência, formigamento, sensibilidade e neuralgia durante o tratamento quimioterápico, todos com influência em algumas atividades cotidianas das mulheres. De acordo com as análises de regressão, a dormência e formigamento nas mãos, neuralgia, dormência nos pés e sensibilidade ao frio foram itens com associação estatística na escala de fragilidade. Conclusão: Este estudo avaliou a ocorrência da NPIQ e o risco de queda em mulheres idosas com diagnóstico de câncer. Apesar de pouco descrito na literatura, foi possível identificar a influência da NPIQ nas atividades cotidianas, com a associação entre os sintomas e o risco de queda, bem como as limitações funcionais no cotidiano da mulher

Introduction: Advances in the areas of health and technology favored the process of demographic transition and increased life expectancy. Consequently, the increase in the elderly population causes an increase in non-communicable chronic diseases, which include cancer, considered the second leading cause of death worldwide. Among the various cancer treatment options, chemotherapy stands out, as during its use the patient may experience different adverse events. One of these events is neurotoxicity, known as chemotherapy-induced peripheral neuropathy (CIPN), which is characterized as an inflammatory or degenerative lesion of the peripheral nerves. It is manifested by typical sensory symptoms, such as loss of sensitivity in the limbs and loss of reflexes, weakness in the hands and feet and dysesthesias, loss of discrimination between touch and temperature (cold and heat), whose clinical manifestations include pain, tingling, shock and burning, and may result in negative consequences for everyday life and make them more vulnerable to falls. Objective: To assess the occurrence of CIPN and the risk of falling in elderly women diagnosed with cancer. Method: Quantitative, descriptive and cross-sectional study, developed with 60 elderly women who underwent chemotherapy treatment for any type of cancer. The data collected were socio-demographic and about cancer, and the following instruments were applied: Fall Risk Score, Edmonton Frail Scale, and the Chemotherapy-Induced Peripheral Neuropathy Assessment Tool (FANPIQ). Data were entered into Microsoft Excel, and analyzed using the Statistical Package for the Social Sciences - SPSS v. 22.0. Descriptive analyzes were performed with mean and standard deviation, analytical and multivariate regression tests. Results: The participants' mean age was 69.57 (SD±7.63) years, 58.3% had arterial hypertension and 30% had diabetes mellitus, 96.7% used some type of medication and 75% had breast cancer. As for the risk of falling, 36.7% of the participants stated that they had already had some type of fall in the last 12 months, with or without injury; however, only 6.7% had some sensory deficit. In the assessment of frailty, 58.3% of the elderly women did not need help to carry out basic activities of daily living, and 48.3% of the participants passed the cognition test. As for the neuropathic symptoms, it evaluated the occurrence of numbness, tingling, sensitivity and neuralgia during chemotherapy treatment, all of which influenced some of the women's daily activities. According to the regression analyses, numbness and tingling in the hands, neuralgia, numbness in the feet and sensitivity to cold were items with statistical association in the frailty scale. Conclusion: This study evaluated the occurrence of CIPN and the risk of falling in elderly women diagnosed with cancer. Although little described in the literature, it was possible to identify the influence of CIPN on daily activities, with the association between symptoms and the risk of falling, as well as functional limitations in women's daily lives

Partnered, adapted argentine tango dance for cancer survivors: A feasibility study and pilot study of efficacy.

BACKGROUND: Neurotoxic cancer treatments can cause chemotherapy-induced peripheral neuropathy and postural control deficits that cancer survivors report as a concern. Exercise-based sensorimotor training has emerged as a promising treatment for symptoms including balance deficits, however, more study is needed to optimize engagement and participation. We evaluated feasibility, satisfaction, and preliminary efficacy of a novel balance training program for cancer survivors: partnered, Adapted Argentine Tango dance (Tango). METHODS: Twenty-two individuals participated (n = 22). Tango classes (1 h) were offered twice/week. At baseline, midpoint (8 classes), and conclusion of the training (15 or 16 classes), we assessed postural control by measuring center-of-pressure (CoP) measures during quiet standing with eyes closed. We also documented attendance, barriers to attendance, and satisfaction (7 point scale; 1 high). At conclusion, we analyzed whether 1) attendance and satisfaction met feasibility criteria; 2) postural control improved among participants who were outside of normal range at baseline; and 3) co-enrolling with a companion increased attendance. FINDINGS: Feasibility criteria were met: more than half of participants attended more than half the classes offered with a mean satisfaction rate of 1.2 (SD 0.4). Those who enrolled with a companion (n = 9) attended more sessions than those who did not (n = 13) (Mann-Whitney U value = 20; p = 0.012). Participants with demonstrated deficits (n = 9) improved in 3 CoP measures at midpoint (i.e., medial-lateral sway, ellipse area, medial-lateral velocity), retaining improvement in 2 CoP measures at endpoint (i.e., medial-lateral sway, ellipse area). INTERPRETATION: Partnered, Adapted Argentine Tango is feasible for cancer survivors and may improve postural control. Enrolling with a companion improved attendance.

Anti-allodynic and anti-inflammatory effects of 17α-hydroxyprogesterone caproate in oxaliplatin-induced peripheral neuropathy.

Chemotherapy-induced peripheral neuropathy is a disabling condition induced by several frequently used chemotherapeutic drugs including the front-line agent oxaliplatin (OXA). Symptoms are predominantly sensory with the development of neuropathic pain. Alternative dosing protocols and treatment discontinuation are the only available therapeutic strategies. The aim of our work was to evaluate the potential of a synthetic derivative of progesterone, 17α-hydroxyprogesterone caproate (HPGC), in the prevention and treatment of OXA-evoked painful neuropathy. We also evaluated glial activation at the dorsal root ganglia (DRG) and spinal cord levels as a possible target mechanism underlying HPGC actions. Male rats were injected with OXA and HPGC following a prophylactic (HPGCp) or therapeutic (HPGCt) scheme (starting either before or after chemotherapy). The development of hypersensitivity and allodynic pain and the expression of neuronal and glial activation markers were evaluated. When compared to control animals, those receiving OXA showed a significant decrease in paw mechanical and thermal thresholds, with the development of allodynia. Animals treated with HPGCp showed patterns of response similar to those detected in control animals, while those treated with HPGCt showed a suppression of both hypersensitivities after HPGC administration. We also observed a significant increase in the mRNA levels of activating transcription factor 3, the transcription factor (c-fos), glial fibrillary acidic protein, ionized calcium binding adaptor protein 1, interleukin 1 beta (IL-1ß) and tumor necrosis factor alpha (TNFα) in DRG and spinal cord of OXA-injected animals, and significantly lower levels in rats receiving OXA and HPGC. These results show that HPGC administration reduces neuronal and glial activation markers and is able to both prevent and suppress OXA-induced allodynia, suggesting a promising therapeutic strategy.

Effects of transcutaneous electrical nerve stimulation on chemotherapy-induced peripheral neuropathy symptoms (CIPN): a preliminary case-control study.

[Purpose] The aim of this double-blind, randomized and placebo-controlled study is to investigate the effects of Transcutaneous Electrical Nerve Stimulation for reducing the side effects of Chemotherapy-induced Peripheral Neuropathy in cancer patients undergoing chemotherapy with oxaloplatin or paclitaxel. [Subjects and Methods] Twenty-four patients were randomly allocated into two groups: active or placebo stimulation. All patients were assessed for pain, numbness/tingiling, frequency of symptoms, and quality of life. The transcutaneous Electrical Nerve Stimulation device was applied daily with modulating frequencies ranging between 7 Hz and 65 Hz in distal limb regions during three cycles of chemotherapy (45 days). The other stimulation parameters were: pulse duration of 200 µsec, intensity at the highest tolerable level, and increases in intensity when it diminished. [Results] The data showed no difference between active or placebo groups in terms of pain, numbness/tingling, frequency of symptoms or impact on daily life activities. [Conclusion] These results suggest that Transcutaneous Electrical Nerve Stimulation applied in the frequency variation mode was not proven to be effective to improve the symptoms of Chemotherapy-induced Peripheral Neuropathy during chemotherapy cycles. There was no worsening of symptoms in subsequent cycles of the onset of symptoms of the disease.

New guidelines for chemotherapy-induced peripheral neuropathy.

The focus of this column is to present topics of interest from a variety of journals to Oncology Nursing Forum readers. The topic of this issue is the release of new and adapted survivorship guidelines from the American Society of Clinical Oncology.