PKC/MEK inhibitors suppress oxaliplatin‐induced neuropathy and potentiate the antitumor effects |
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| Authors: | Masanobu Tsubaki Tomoya Takeda Tadahumi Tani Hirotaka Shimaoka Naohiro Suzuyama Kotaro Sakamoto Arisa Fujita Naoki Ogawa Tatsuki Itoh Motohiro Imano Yoshinori Funakami Seiji Ichida Takao Satou Shozo Nishida |
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| Affiliation: | 1. Division of Pharmacotherapy, Kinki University School of Pharmacy, Kowakae, Higashi‐Osaka, Japan;2. Department of Pharmacy, Sakai City Hospital, Sakai, Osaka, Japan;3. Department of Food Science and Nutrition, Kinki University School of Agriculture, Nara, Nara, Japan;4. Department of Surgery, Kinki University School of Medicine, Osakasayama, Osaka, Japan;5. Division of Biochemistry, Kinki University School of Pharmacy, Kowakae, Higashi‐Osaka, Japan;6. Department of Pathology, Kinki University School of Medicine, Osakasayama, Osaka, Japan |
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| Abstract: | 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. |
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| Keywords: | PKC MEK oxaliplatin neuropathy |
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