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

• Published in: International journal of cancer Vol. 137; no. 1; pp. 243 - 250
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.07.2015
• Subjects: Animals; Benzamides - administration & dosage; Benzamides - pharmacology; Cancer; Cell Line, Tumor; Cell Proliferation - drug effects; Colorectal cancer; Colorectal Neoplasms - drug therapy; Diphenylamine - administration & dosage; Diphenylamine - analogs & derivatives; Diphenylamine - pharmacology; Disease Models, Animal; Drug Synergism; Hyperalgesia - chemically induced; Hyperalgesia - drug therapy; Hyperalgesia - pathology; Kinases; Male; MAP Kinase Signaling System - drug effects; Medical research; MEK; Mice; Mice, Inbred BALB C; neuropathy; Organoplatinum Compounds - administration & dosage; Organoplatinum Compounds - adverse effects; oxaliplatin; PKC; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - pharmacology; Proteins; Spinal Cord - drug effects; Spinal Cord - pathology; Tamoxifen - administration & dosage; Tamoxifen - pharmacology; PKC; neuropathy; oxaliplatin; MEK
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.29367

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. What's new? Oxaliplatin is a key component in adjuvant and palliative therapy for colorectal cancer, but its use is limited by the development of neuropathy, which typically is unresponsive to treatment. Following on previous work in which protein kinase C (PKC) activation was implicated in oxaliplatin‐induced neuropathy, the present report suggests that PKC and MEK inhibitors may be able to block the neuropathic side effects. Inhibition was effected in the lumbar spinal cords of mice, via the PKC/ERK/c‐Fos pathway. PKC and MEK inhibitors were also found to act synergistically to potentiate the tumor suppressive effects of oxaliplatin.