Novel therapies for cancer-induced bone pain

被引:2
作者
Haroun, Rayan [1 ]
Gossage, Samuel J. [1 ]
Iseppon, Federico [1 ]
Fudge, Alexander [1 ]
Caxaria, Sara [2 ]
Arcangeletti, Manuel [1 ]
Leese, Charlotte [3 ]
Davletov, Bazbek [3 ]
Cox, James J. [1 ]
Sikandar, Shafaq [2 ]
Welsh, Fraser [4 ]
Chessell, Iain P. [4 ]
Wood, John N. [1 ]
机构
[1] Univ Coll London UCL, Wolfson Inst Biomed Res WIBR, Mol Nocicept Grp, London WC1E 6BT, England
[2] Queen Mary Univ London, William Harvey Res Inst, Barts & London Sch Med & Dent, London, England
[3] Univ Sheffield, Dept Biomed Sci, Sheffield S10 2TN, S Yorkshire, England
[4] AstraZeneca, BioPharmaceut R&D, Neurosci Discovery Ctr, Biomed Campus,1 Francis Crick Ave, Cambridge CB2 0AA, England
关键词
Cancer-induced bone pain; Dorsal root ganglia; Acid-sensing ion channels; Voltage-gated sodium channels; Modified botulinum compounds; Tumor necrosis factor alpha; Nerve growth factor; NECROSIS-FACTOR-ALPHA; NERVE GROWTH-FACTOR; RESISTANT SODIUM-CHANNELS; RAT SENSORY NEURONS; CAPSAICIN RECEPTOR; BOTULINUM NEUROTOXIN; SKELETAL PAIN; MURINE MODEL; DESTRUCTION; MORPHINE;
D O I
10.1016/j.ynpai.2024.100167
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
Cancer pain is a growing problem, especially with the substantial increase in cancer survival. Reports indicate that bone metastasis, whose primary symptom is bone pain, occurs in 65-75% of patients with advanced breast or prostate cancer. We optimized a preclinical in vivo model of cancer-induced bone pain (CIBP) involving the injection of Lewis Lung Carcinoma cells into the intramedullary space of the femur of C57BL/6 mice or transgenic mice on a C57BL/6 background. Mice gradually reduce the use of the affected limb, leading to altered weight bearing. Symptoms of secondary cutaneous heat sensitivity also manifest themselves. Following optimization, three potential analgesic treatments were assessed; 1) single ion channel targets (targeting the voltage-gated sodium channels Na(V)1.7, Na(V)1.8, or acid-sensing ion channels), 2) silencing mu -opioid receptor-expressing neurons by modified botulinum compounds, and 3) targeting two inflammatory mediators simultaneously (nerve growth factor (NGF) and tumor necrosis factor (TNF)). Unlike global Na(V)1.8 knockout mice which do not show any reduction in CIBP-related behavior, embryonic conditional Na(V)1.7 knockout mice in sensory neurons exhibit a mild reduction in CIBP-linked behavior. Modified botulinum compounds also failed to cause a detectable analgesic effect. In contrast, inhibition of NGF and/or TNF resulted in a significant reduction in CIBP-driven weight-bearing alterations and prevented the development of secondary cutaneous heat hyperalgesia. Our results support the inhibition of these inflammatory mediators, and more strongly their dual inhibition to treat CIBP, given the superiority of combination therapies in extending the time needed to reach limb use score zero in our CIBP model.
引用
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页数:12
相关论文
共 70 条
[1]   The tetrodotoxin-resistant sodium channel SNS has a specialized function in pain pathways [J].
Akopian, AN ;
Souslova, V ;
England, S ;
Okuse, K ;
Ogata, N ;
Ure, J ;
Smith, A ;
Kerr, BJ ;
McMahon, SB ;
Boyce, S ;
Hill, R ;
Stanfa, LC ;
Dickenson, AH ;
Wood, JN .
NATURE NEUROSCIENCE, 1999, 2 (06) :541-548
[2]   Elevated levels of proinflammatory cytokines in the semen of patients with chronic prostatitis chronic pelvic pain syndrome [J].
Alexander, RB ;
Ponniah, S ;
Hasday, J ;
Hebel, JR .
UROLOGY, 1998, 52 (05) :744-749
[3]   Stapling of the botulinum type A protease to growth factors and neuropeptides allows selective targeting of neuroendocrine cells [J].
Arsenault, Jason ;
Ferrari, Enrico ;
Niranjan, Dhevahi ;
Cuijpers, Sabine A. G. ;
Gu, Chunjing ;
Vallis, Yvonne ;
O'Brien, John ;
Davletov, Bazbek .
JOURNAL OF NEUROCHEMISTRY, 2013, 126 (02) :223-233
[4]   Painful and painless channelopathies [J].
Bennett, David L. H. ;
Woods, C. Geoffrey .
LANCET NEUROLOGY, 2014, 13 (06) :587-599
[5]   Subcutaneous tanezumab for osteoarthritis of the hip or knee: efficacy and safety results from a 24-week randomised phase III study with a 24-week follow-up period [J].
Berenbaum, Francis ;
Blanco, Francisco J. ;
Guermazi, Ali ;
Miki, Kenji ;
Yamabe, Takaharu ;
Viktrup, Lars ;
Junor, Rod ;
Carey, William ;
Brown, Mark T. ;
West, Christine R. ;
Verburg, Kenneth M. .
ANNALS OF THE RHEUMATIC DISEASES, 2020, 79 (06) :800-810
[6]   cAMP-dependent protein kinase regulates desensitization of the capsaicin receptor (VR1) by direct phosphorylation [J].
Bhave, G ;
Zhu, WG ;
Wang, HB ;
Brasier, DJ ;
Oxford, GS ;
Gereau, RW .
NEURON, 2002, 35 (04) :721-731
[7]   Prospective administration of anti-nerve growth factor treatment effectively suppresses functional connectivity alterations after cancer-induced bone pain in mice [J].
Buehlmann, David ;
Ielacqua, Giovanna Diletta ;
Xandry, Jael ;
Rudin, Markus .
PAIN, 2019, 160 (01) :151-159
[8]  
Chin Hong, 2015, Fed Pract, V32, P24
[9]   Bradykinin and nerve growth factor release the capsaicin receptor from PtdIns(4,5)P2-mediated inhibition [J].
Chuang, HH ;
Prescott, ED ;
Kong, HY ;
Shields, S ;
Jordt, SE ;
Basbaum, AI ;
Chao, MV ;
Julius, D .
NATURE, 2001, 411 (6840) :957-962
[10]   Metastatic bone disease: clinical features, pathophysiology and treatment strategies [J].
Coleman, RE .
CANCER TREATMENT REVIEWS, 2001, 27 (03) :165-176