Selective inhibition of JNK with a peptide inhibitor attenuates pain hypersensitivity and tumor growth in a mouse skin cancer pain model.
Cancer pain significantly affects the quality of cancer patients, and current treatments for this pain are limited. C-Jun N-terminal kinase (JNK) has been implicated in tumor growth and neuropathic pain sensitization. We investigated the role of JNK in cancer pain and tumor growth in a skin cancer pain model. Injection of luciferase-transfected B16-Fluc melanoma cells into a hindpaw of mouse induced robust tumor growth, as indicated by increase in paw volume and fluorescence intensity. Pain hypersensitivity in this model developed rapidly (<5 days) and reached a peak in 2 weeks, and was characterized by mechanical allodynia and heat hyperalgesia. Tumor growth was associated with JNK activation in tumor mass, dorsal root ganglion (DRG), and spinal cord and a peripheral neuropathy, such as loss of nerve fibers in the hindpaw skin and induction of ATF-3 expression in DRG neurons. Repeated systemic injections of D-JNKI-1 (6 mg/kg, i.p.), a selective and cell-permeable peptide inhibitor of JNK, produced an accumulative inhibition of mechanical allodynia and heat hyperalgesia. A bolus spinal injection of D-JNKI-1 also inhibited mechanical allodynia. Further, JNK inhibition suppressed tumor growth in vivo and melanoma cell proliferation in vitro. In contrast, repeated injections of morphine (5 mg/kg), a commonly used analgesic for terminal cancer, produced analgesic tolerance after 1 day and did not inhibit tumor growth. Our data reveal a marked peripheral neuropathy in this skin cancer model and important roles of the JNK pathway in cancer pain development and tumor growth. JNK inhibitors such as D-JNKI-1 may be used to treat cancer pain.
Gao
Yong-Jing
YJ
Pain Research Center, Department of Anesthesiology, Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, Medical Research Building, Room 604, Boston, MA 02115, USA.
Cheng
Jen-Kun
JK
Zeng
Qing
Q
Xu
Zhen-Zhong
ZZ
Decosterd
Isabelle
I
Xu
Xiaoyin
X
Ji
Ru-Rong
RR
D051700:Activating Transcription Factor 3 / Q000378:metabolism; D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006930:Hyperalgesia / Q000188:drug therapy / Q000201:enzymology / Q000209:etiology; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D008545:Melanoma / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology; D051379:Mice; D008810:Mice, Inbred C57BL; D009020:Morphine / Q000494:pharmacology; D010146:Pain / Q000188:drug therapy* / Q000201:enzymology / Q000209:etiology; D010147:Pain Measurement; D010455:Peptides / Q000494:pharmacology / Q000627:therapeutic use; D010523:Peripheral Nervous System Diseases / Q000201:enzymology / Q000209:etiology / Q000503:physiopathology; D011984:Sensory Receptor Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D012878:Skin Neoplasms / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology
D051700:Activating Transcription Factor 3; D000701:Analgesics, Opioid; C103002:Atf3 protein, mouse; D004791:Enzyme Inhibitors; D010455:Peptides; D009020:Morphine; D048031:JNK Mitogen-Activated Protein Kinases