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

Tsubaki, Masanobu; Takeda, Tomoya; Tani, Tadahumi; Shimaoka, Hirotaka; Suzuyama, Naohiro; Sakamoto, Kotaro; Fujita, Arisa; Ogawa, Naoki; Itoh, Tatsuki; Imano, Motohiro; Funakami, Yoshinori; Ichida, Seiji; Satou, Takao; Nishida, Shozo

doi:10.1002/ijc.29367

Cited by 24 publications

(22 citation statements)

References 23 publications

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“…In addition, the analgesic effect of the combined application of these inhibitors was not significantly different from that of the application of either inhibitor alone. Therefore, these data support the implication that PKC and ERK1/2 are involved in the same signaling pathway of visceral pain, rather than in parallel pathways [ 26 – 31 ].…”

Section: Discussionsupporting

confidence: 72%

Gabapentin Effects on PKC-ERK1/2 Signaling in the Spinal Cord of Rats with Formalin-Induced Visceral Inflammatory Pain

Zhang

Guo

et al. 2015

PLoS ONE

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Currently, the clinical management of visceral pain remains unsatisfactory for many patients suffering from this disease. While preliminary animal studies have suggested the effectiveness of gabapentin in successfully treating visceral pain, the mechanism underlying its analgesic effect remains unclear. Evidence from other studies has demonstrated the involvement of protein kinase C (PKC) and extracellular signal-regulated kinase1/2 (ERK1/2) in the pathogenesis of visceral inflammatory pain. In this study, we tested the hypothesis that gabapentin produces analgesia for visceral inflammatory pain through its inhibitory effect on the PKC-ERK1/2 signaling pathway. Intracolonic injections of formalin were performed in rats to produce colitis pain. Our results showed that visceral pain behaviors in these rats decreased after intraperitoneal injection of gabapentin. These behaviors were also reduced by intrathecal injections of the PKC inhibitor, H-7, and the ERK1/2 inhibitor, PD98059. Neuronal firing of wide dynamic range neurons in L6–S1 of the rat spinal cord dorsal horn were significantly increased after intracolonic injection of formalin. This increased firing rate was inhibited by intraperitoneal injection of gabapentin and both the individual and combined intrathecal application of H-7 and PD98059. Western blot analysis also revealed that PKC membrane translocation and ERK1/2 phosphorylation increased significantly following formalin injection, confirming the recruitment of PKC and ERK1/2 during visceral inflammatory pain. These effects were also significantly reduced by intraperitoneal injection of gabapentin. Therefore, we concluded that the analgesic effect of gabapentin on visceral inflammatory pain is mediated through suppression of PKC and ERK1/2 signaling pathways. Furthermore, we found that the PKC inhibitor, H-7, significantly diminished ERK1/2 phosphorylation levels, implicating the involvement of PKC and ERK1/2 in the same signaling pathway. Thus, our results suggest a novel mechanism of gabapentin-mediated analgesia for visceral inflammatory pain through a PKC-ERK1/2 signaling pathway that may be a future therapeutic target for the treatment of visceral inflammatory pain.

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Section: Discussionsupporting

confidence: 72%

Gabapentin Effects on PKC-ERK1/2 Signaling in the Spinal Cord of Rats with Formalin-Induced Visceral Inflammatory Pain

Zhang

Guo

et al. 2015

PLoS ONE

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“…Notably, it has been shown that oxaliplatin-induced peripheral neurotoxicity may be mediated by early p38 and ERK1/2 activation in the dorsal root ganglia neurons (Hector et al, 2001 ; Scuteri et al, 2009 ). In support of this conclusion, another study demonstrated that a MEK1/2 inhibitor PD0325901 was able to suppress the oxaliplatin-induced neuropathy and synergistically potentiated the tumor suppressive effects of oxaliplatin in a colon carcinoma allograft mouse model (Tsubaki et al, 2015 ). Considering its strong inhibitory effects against multiple kinases activation in CRC cells observed in our study, it seems plausible to hypothesize that ursolic acid may also play a neuroprotective role against oxaliplatin-induced neuropathy while enhancing its cytotoxicity against tumor cells.…”

Section: Discussionmentioning

confidence: 85%

Ursolic acid synergistically enhances the therapeutic effects of oxaliplatin in colorectal cancer

et al. 2016

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Oxaliplatin is a key drug in chemotherapy of colorectal cancer (CRC). However, its efficacy is unsatisfied due to drug resistance of cancer cells. In this study, we tested whether a natural agent, ursolic acid, was able to enhance the efficacy of oxaliplatin for CRC. Four CRC cell lines including SW480, SW620, LoVo, and RKO were used as in vitro models, and a SW620 xenograft mouse model was used in further in vivo study. We found that ursolic acid inhibited proliferation and induced apoptosis of all four cells and enhanced the cytotoxicity of oxaliplatin. This effect was associated with down-regulation of Bcl-xL, Bcl-2, survivin, activation of caspase-3, 8, 9, and inhibition of KRAS expression and BRAF, MEK1/2, ERK1/2, p-38, JNK, AKT, IKKα, IκBα, and p65 phosphorylation of the MAPK, PI3K/AKT, and NF-κB signaling pathways. The two agents also showed synergistic effects against tumor growth in vivo. In addition, ursolic acid restored liver function and body weight of the mice treated with oxaliplatin. Thus, we concluded that ursolic acid could enhance the therapeutic effects of oxaliplatin against CRC both in vitro and in vivo, which offers an effective strategy to minimize the burden of oxaliplatin-induced adverse events and provides the groundwork for a new clinical strategy to treat CRC.

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“…Moreover, by using specific inhibitors of the different MAPKs, it has been demonstrated that the platinum-induced neuronal apoptosis is mediated by early p38 and ERK1/2 activation [14]. In in-vivo studies, oxaliplatin has shown to increase p38 phosphorylation at 0.5 and 4 hours after the treatment [22], or protein kinase C (PKC) phosphorylation, ERK1/2 phosphorylation, and c-fos expression on day 14 after the treatment [23], in the spinal cord of oxaliplatin-induced neuropathy mouse model. These results and our findings suggest a role for MAPKs including ERK in the generation and development of oxaliplatin-induced peripheral neuropathy.…”

Section: Discussionmentioning

confidence: 99%

Upregulation of ERK phosphorylation in rat dorsal root ganglion neurons contributes to oxaliplatin-induced chronic neuropathic pain

et al. 2019

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Oxaliplatin is the first-line chemotherapy for metastatic colorectal cancer. Unlike other platinum anticancer agents, oxaliplatin does not result in significant renal impairment and ototoxicity. Oxaliplatin, however, has been associated with acute and chronic peripheral neuropathies. Despite the awareness of these side-effects, the underlying mechanisms are yet to be clearly established. Therefore, in this study, we aimed to understand the factors involved in the generation of chronic neuropathy elicited by oxaliplatin treatment. We established a rat model of oxaliplatin-induced neuropathic pain (4 mg kg-1 intraperitoneally). The paw withdrawal thresholds were assessed at different time-points after the treatment, and a significant decrease was observed 3 and 4 weeks after oxaliplatin treatment as compared to the vehicle treatment (4.4 ± 1.0 vs. 16.0 ± 4.1 g; P < 0.05 and 4.4 ± 0.7 vs. 14.8 ± 3.1 g; P < 0.05, respectively). We further evaluated the role of different mitogen-activated protein kinases (MAPKs) pathways in the pathophysiology of neuropathic pain. Although the levels of total extracellular signal-regulated kinase (ERK) 1/2 in the dorsal root ganglia (DRG) were not different between oxaliplatin and vehicle treatment groups, phosphorylated ERK (p-ERK) 1/2 was up-regulated up to 4.5-fold in the oxaliplatin group. Administration of ERK inhibitor PD98059 (6 μg day-1 intrathecally) inhibited oxaliplatin-induced ERK phosphorylation and neuropathic pain. Therefore, upregulation of p-ERK by oxaliplatin in rat DRG and inhibition of mechanical allodynia by an ERK inhibitor in the present study may provide a better understanding of intracellular molecular alterations associated with oxaliplatin-induced neuropathic pain and help in the development of potential therapeutics.

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

Cited by 24 publications

References 23 publications

Gabapentin Effects on PKC-ERK1/2 Signaling in the Spinal Cord of Rats with Formalin-Induced Visceral Inflammatory Pain

Gabapentin Effects on PKC-ERK1/2 Signaling in the Spinal Cord of Rats with Formalin-Induced Visceral Inflammatory Pain

Ursolic acid synergistically enhances the therapeutic effects of oxaliplatin in colorectal cancer

Upregulation of ERK phosphorylation in rat dorsal root ganglion neurons contributes to oxaliplatin-induced chronic neuropathic pain

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