Supraspinal role of protein kinase C in oxaliplatin-induced neuropathy in rat

Norcini, Monica; Vivoli, Elisa; Galeotti, Nicoletta; Bianchi, Enrica; Bartolini, Alessandro; Ghelardini, Carla

doi:10.1016/j.pain.2009.07.017

Cited by 50 publications

(35 citation statements)

References 20 publications

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“…Our group has demonstrated an oxaliplatin-dependent alteration at the spinal and supraspinal levels in the rat of PKCγ [10] . Here, we confirmed the previous data in oxaliplatin-treated mice supporting a correlation between enhanced mechanical nociception with increased phosphorylation of PKCγ in PAG and thalamus brain regions.…”

Section: Discussionmentioning

confidence: 91%

“…Given the known molecular interactions between the GAP43 mRNA, cytoskeleton apparatus and ELAV proteins, we sought to investigate the role of the HuD protein in oxaliplatin-induced neuropathy and the possible HuD-mediated modulation of these regulatory and structural proteins in this study. Increased phosphorylation of protein kinase C (PKC) γ isoform within the thalamus and periaqueductal grey (PAG) was observed after oxaliplatin chronic treatment, and the hyperalgesic effect was reversed in the presence of selective PKC inhibitor calphostin C, supraspinally administered [10] . In order to relate changes at the molecular and cellular levels to the development of sensory alterations, we also examined a relationship between the PKC pathway and GAP43, known as indicator of injury-induced molecular changes that could be related to the alterations in sensory function.…”

Section: Introductionmentioning

confidence: 99%

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Altered Expression of Cytoskeletal and Axonal Proteins in Oxaliplatin-Induced Neuropathy

Sanna¹,

Ghelardini²,

Galeotti³

2016

Pharmacology

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Background: Oxaliplatin is a platinum compound widely used in the treatment of some solid tumors. Despite its usefulness, oxaliplatin-associated neurotoxicity represents the main dose-limiting factor of this drug. This study examined the structural neuronal effects of oxaliplatin treatment in spinal and supraspinal levels. Methods: Protein expression was investigated in the mouse cortex, thalamus, periaqueductal grey (PAG) matter and spinal cord (SC) by Western blotting. Thermal nociception was assessed by the hot plate test. Results: Results indicate a reduction in the levels of growth associated protein-43 (GAP43) in the cortex and SC areas at the end of thermal hyperalgesic response, while a decrease in neurofilament-H (NfH) phosphorylation was observed in the SC on day 21 when the pain-related manifestation reaches the neurotoxic peak. Counteracting phosphorylated NfH content increases in the SC and cortex regions at day 28 as a result of the beginning of neuro-regeneration process. We also revealed that the levels of HuD, a neuronal-specific RNA-binding protein, decreased, demonstrating the same temporal and regional expression pattern of GAP43. Oxaliplatin chronic treatment induced a region-specific upregulation of γ isoform of protein kinase C (PKC) within thalamus and PAG, and the administration of a PKC inhibitor suggests that PKC activity in these brain regions must be required to maintain the thermal hyperalgesic state. Conclusions: These results suggest that changes in the protein levels of the regulatory and structural proteins are due to oxaliplatin-induced neurotoxicity and imply that there is a direct link between structural changes in the central nervous system and chemotherapy-induced neurotoxicity.

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Section: Discussionmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Altered Expression of Cytoskeletal and Axonal Proteins in Oxaliplatin-Induced Neuropathy

Sanna¹,

Ghelardini²,

Galeotti³

2016

Pharmacology

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“…Oxaliplatin-induced neuropathy was shown to be involved in the activation of PKC within the thalamus and periaqueductal area in the brain. 10 In addition, increases in ERK1/2 phosphorylation and c-Fos expression in the spinal cord have been associated with chronic pain. 17,18 Previous studies have established that activation of PKC in the spinal cord dorsal horn plays a critical role in the transmission of nociceptive signals following mustard oil (TRPA1 activator) application.…”

Section: Discussionmentioning

confidence: 99%

“…8,9 Oxaliplatin induces mechanical allodynia by inducing an upregulation of specific g isoforms of PKC and increasing phosphorylation of the g/E PKC isoforms within the thalamus and periaqueductal area in the brain. 10 In addition, oxaliplatin induces apoptosis by activating extracellular signal-regulated kinases 1/2 (ERK1/2) in rat dorsal root ganglia cells. 11 These findings suggested that neuropathy associated with oxaliplatin may be mediated by PKC and ERK1/2 activation in the brain or spinal cord.…”

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confidence: 99%

PKC/MEK inhibitors suppress oxaliplatin‐induced neuropathy and potentiate the antitumor effects

Tsubaki

Takeda

Tani

et al. 2014

Intl Journal of Cancer

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Oxaliplatin is a key drug commonly used in colorectal cancer treatment. Despite high clinical efficacy, its therapeutic application is limited by common, dose-limiting occurrence of neuropathy. As usual symptomatic neuropathy treatments fail to improve the patients' condition, there is an urgent need to advance our understanding of the pathogenesis of neuropathy to propose effective therapy and ensure adequate pain management. Oxaliplatin-induced neuropathy was recently reported to be associated with protein kinase C (PKC) activation. It is unclear, however, whether PKC inhibition can prevent neuropathy. In our current studies, we found that a PKC inhibitor, tamoxifen, inhibited oxaliplatin-induced neuropathy via the PKC/ extracellular signal-regulated kinase (ERK)/c-Fos pathway in lumbar spinal cords (lumbar segments 4-6). Additionally, tamoxifen was shown to act in synergy with oxaliplatin to inhibit growth in tumor cells-implanted mice. Moreover, mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor, PD0325901, suppressed oxaliplatin-induced neuropathy and enhanced oxaliplatin efficacy. Our results indicate that oxaliplatin-induced neuropathy is associated with PKC/ERK/c-Fos pathway in lumbar spinal cord. Additionally, we demonstrate that disruption of this pathway by PKC and MEK inhibitors suppresses oxaliplatin-induced neuropathy, thereby suggesting that PKC and MEK inhibitors may be therapeutically useful in preventing oxaliplatin-induced neuropathy and could aid in combination antitumor pharmacotherapy.Oxaliplatin, a third-generation organoplatinum compound, has become the principal chemotherapy agent used in combination with 5-fluorouracil and leucovorin against colorectal cancer in both adjuvant and palliative therapy.1 However, neuropathy associated with oxaliplatin use is the predominant reason for dose modification, treatment schedule extension and termination of therapy.2 Oxaliplatin induces two different forms of neuropathy.3 A dose-limiting sensory neuropathy occurs at a cumulative dose above 540-850 mg/m 2 and may develop gradually following oxaliplatin treatment. 4A transient, acute syndrome consisting of cold-induced paraesthesia, dysesthesia or pain in the hands, feet, face and perioral regions appears in 80% of patients during the first or second cycle. 4 Current therapeutic options for alleviating neuropathy are mainly limited to drugs approved for other pain conditions, and none of the current agents proven to provide relief. 5 As chemotherapy becomes more effective, the number of cancer survivors is likely to increase, and neuropathy will become an important factor affecting their quality of life. Thus, it is of critical importance to elucidate the mechanism of oxaliplatin-induced neuropathy and consequently develop effective treatment strategies for this debilitating syndrome.Temperature-activated transient receptor potential (TRP) ion channels play important roles in pain sensation. Two particular TRP channels, TRPM8 and TRPA1, have been linked to the sensation of cold. Recently, i...

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“…In the previous study, repeated administration of oxaliplatin caused cold hyperalgesia in the early phase and mechanical allodynia in the late phase (2 weeks after first administration). [25][26][27] Conversely, cold hyperalgesia/allodynia was not observed in the NC-4016-treated rats. Oxalate is well known as a chelator of both Ca2 were shown to decrease oxaliplatin-induced neuropathy without affecting anticancer efficacy.…”

Section: Discussionmentioning

confidence: 99%

Assessment of antitumor activity and acute peripheral neuropathy of 1,2-diaminocyclohexane platinum (II)-incorporating micelles (NC-4016)

Ueno¹,

Endo²,

Hori³

et al. 2014

IJN

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Oxaliplatin, a third-generation platinum compound incorporating oxalate and 1,2-diaminocyclohexane platinum, has been widely used in chemotherapy regimens for the treatment of metastatic colorectal cancer. Because of its wide spectrum of antitumor activity, oxaliplatin has been applied for the treatment of other carcinomas. However, the antitumor activity of single-agent oxaliplatin is insufficient. To increase its antitumor effects, polymeric micellar nanoparticles incorporating 1,2-diaminocyclohexane platinum (NC-4016) have been developed. The present study was designed to evaluate the efficacy of NC-4016 and its association with peripheral neuropathy, which is a primary dose-limiting factor in oxaliplatin therapy. The in vitro antitumor activity of NC-4016 was investigated using human carcinoma cell lines. To investigate the antitumor effects of NC-4016 in vivo, nude mice bearing the human carcinoma cell line KB were administered NC-4016 or oxaliplatin. The in vitro growth-inhibiting effect of NC-4016 was significantly weaker than that of oxaliplatin. However, the antitumor efficacy of NC-4016 was superior to that of oxaliplatin in vivo. Moreover, we compared the severity of peripheral neuropathy induced by oxaliplatin and NC-4016 in a rat model. Oxaliplatin, NC-4016, or 5% glucose (control) were administered by a single tail vein injection. In the oxaliplatin-treated rats, neither mechanical nor heat allodynia was observed during the experimental period, whereas cold hyperalgesia/allodynia was observed from day 1 to 7. Conversely, cold hyperalgesia/allodynia was not observed in the NC-4016-treated rats. The present study demonstrated that the antitumor efficacy of NC-4016 was superior to that of oxaliplatin in a mouse model of human carcinoma cell line KB. In addition, NC-4016-treated rats did not develop acute cold hypersensitivity, which is frequently experienced by patients after oxaliplatin administration.

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Supraspinal role of protein kinase C in oxaliplatin-induced neuropathy in rat

Cited by 50 publications

References 20 publications

Altered Expression of Cytoskeletal and Axonal Proteins in Oxaliplatin-Induced Neuropathy

Altered Expression of Cytoskeletal and Axonal Proteins in Oxaliplatin-Induced Neuropathy

PKC/MEK inhibitors suppress oxaliplatin‐induced neuropathy and potentiate the antitumor effects

Assessment of antitumor activity and acute peripheral neuropathy of 1,2-diaminocyclohexane platinum (II)-incorporating micelles (NC-4016)

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