Inhibition of P38-MAPK Signaling Pathway Attenuates Breast Cancer Induced Bone Pain and Disease Progression in a Murine Model of Cancer-induced Bone Pain

Overview

Journal Mol Pain

Date 2011 Oct 22

PMID 22014040

Citations 17

Authors

Devki Sukhtankar

Alec Okun

Anupama Chandramouli

Mark A Nelson

Todd W Vanderah

Anne E Cress

Frank Porreca

Tamara King

Affiliations

Soon will be listed here.

Abstract

Background: Mechanisms driving cancer-induced bone pain are poorly understood. A central factor implicated to be a key player in the process of tumorigenesis, osteoclastogenesis and nociception is p38 MAPK. We determined the role of p38 MAPK in a mouse model of breast cancer induced bone pain in which mixed osteolytic and osteoblastic remodeling occurs.

Results: In cancer-treated mice, acute as well as chronic inhibition of p38 MAPK with SB203580 blocked flinching and guarding behaviors in a dose-dependent manner whereas no effect on thresholds to tactile stimuli was observed. Radiographic analyses of bones demonstrated that chronic inhibition of p38 MAPK reduced bone loss and incidence of spontaneous fracture in cancer-treated mice. Histological analysis of bones collected from mice treated with the p38 MAPK inhibitor showed complete absence of osteoblastic growth in the intramedullary space as well as significantly reduced tumor burden.

Conclusions: Blockade of non-evoked pain behaviors but not hypersensitivity suggests differences in the underlying mechanisms of specific components of the pain syndrome and a possibility to individualize aspects of pain management. While it is not known whether the role of p38 MAPK signaling can be expanded to other cancers, the data suggest a need for understanding molecular mechanisms and cellular events that initiate and maintain cancer-induced bone pain for effective management for both ongoing pain as well as breakthrough pain.

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References

Kim S, Bae J, Kim J, Lee H, Lee K, Kim D . Activation of p38 MAP kinase in the rat dorsal root ganglia and spinal cord following peripheral inflammation and nerve injury. Neuroreport. 2002; 13(18):2483-6. DOI: 10.1097/00001756-200212200-00021. View

Obata K, Katsura H, Mizushima T, Yamanaka H, Kobayashi K, Dai Y . TRPA1 induced in sensory neurons contributes to cold hyperalgesia after inflammation and nerve injury. J Clin Invest. 2005; 115(9):2393-401. PMC: 1187934. DOI: 10.1172/JCI25437. View

Kumar S, Votta B, Rieman D, Badger A, Gowen M, Lee J . IL-1- and TNF-induced bone resorption is mediated by p38 mitogen activated protein kinase. J Cell Physiol. 2001; 187(3):294-303. DOI: 10.1002/jcp.1082. View

Peters C, Ghilardi J, Keyser C, Kubota K, Lindsay T, Luger N . Tumor-induced injury of primary afferent sensory nerve fibers in bone cancer pain. Exp Neurol. 2005; 193(1):85-100. DOI: 10.1016/j.expneurol.2004.11.028. View

Svensson C, Marsala M, Westerlund A, Calcutt N, Campana W, Freshwater J . Activation of p38 mitogen-activated protein kinase in spinal microglia is a critical link in inflammation-induced spinal pain processing. J Neurochem. 2003; 86(6):1534-44. DOI: 10.1046/j.1471-4159.2003.01969.x. View

Zhang F, Cao J, Zhang L, Zeng Y . Activation of p38 mitogen-activated protein kinase in spinal cord contributes to chronic constriction injury-induced neuropathic pain. Sheng Li Xue Bao. 2005; 57(5):545-51. View

Vit J, Ohara P, Tien D, Fike J, Eikmeier L, Beitz A . The analgesic effect of low dose focal irradiation in a mouse model of bone cancer is associated with spinal changes in neuro-mediators of nociception. Pain. 2005; 120(1-2):188-201. DOI: 10.1016/j.pain.2005.10.033. View

Keller E, Brown J . Prostate cancer bone metastases promote both osteolytic and osteoblastic activity. J Cell Biochem. 2004; 91(4):718-29. DOI: 10.1002/jcb.10662. View

DIXON W . Efficient analysis of experimental observations. Annu Rev Pharmacol Toxicol. 1980; 20:441-62. DOI: 10.1146/annurev.pa.20.040180.002301. View

10.

Garry E, Delaney A, Blackburn-Munro G, Dickinson T, Moss A, Nakalembe I . Activation of p38 and p42/44 MAP kinase in neuropathic pain: involvement of VPAC2 and NK2 receptors and mediation by spinal glia. Mol Cell Neurosci. 2005; 30(4):523-37. DOI: 10.1016/j.mcn.2005.08.016. View

11.

Chen L, He H, Li H, Zheng J, Heng W, You J . ERK1/2 and p38 pathways are required for P2Y receptor-mediated prostate cancer invasion. Cancer Lett. 2004; 215(2):239-47. DOI: 10.1016/j.canlet.2004.05.023. View

12.

Raingeaud J, Gupta S, Rogers J, Dickens M, Han J, Ulevitch R . Pro-inflammatory cytokines and environmental stress cause p38 mitogen-activated protein kinase activation by dual phosphorylation on tyrosine and threonine. J Biol Chem. 1995; 270(13):7420-6. DOI: 10.1074/jbc.270.13.7420. View

13.

Ji R, Samad T, Jin S, Schmoll R, Woolf C . p38 MAPK activation by NGF in primary sensory neurons after inflammation increases TRPV1 levels and maintains heat hyperalgesia. Neuron. 2002; 36(1):57-68. DOI: 10.1016/s0896-6273(02)00908-x. View

14.

Cohen M, Easley M, Ellis C, Hughes B, Ownby K, Rashad B . Cancer pain management and the JCAHO's pain standards: an institutional challenge. J Pain Symptom Manage. 2003; 25(6):519-27. DOI: 10.1016/s0885-3924(03)00068-x. View

15.

Mizushima T, Obata K, Yamanaka H, Dai Y, Fukuoka T, Tokunaga A . Activation of p38 MAPK in primary afferent neurons by noxious stimulation and its involvement in the development of thermal hyperalgesia. Pain. 2004; 113(1-2):51-60. DOI: 10.1016/j.pain.2004.09.038. View

16.

Luger N, Honore P, Sabino M, Schwei M, Rogers S, Mach D . Osteoprotegerin diminishes advanced bone cancer pain. Cancer Res. 2001; 61(10):4038-47. View

17.

Tominaga M, Tominaga T . Structure and function of TRPV1. Pflugers Arch. 2005; 451(1):143-50. DOI: 10.1007/s00424-005-1457-8. View

18.

Pasquet S, Watson S . Direct inhibition of cyclooxygenase-1 and -2 by the kinase inhibitors SB 203580 and PD 98059. SB 203580 also inhibits thromboxane synthase. J Biol Chem. 1998; 273(44):28766-72. DOI: 10.1074/jbc.273.44.28766. View

19.

Cui X, Dai Y, Wang S, Yamanaka H, Kobayashi K, Obata K . Differential activation of p38 and extracellular signal-regulated kinase in spinal cord in a model of bee venom-induced inflammation and hyperalgesia. Mol Pain. 2008; 4:17. PMC: 2391153. DOI: 10.1186/1744-8069-4-17. View

20.

Matsumoto M, Sudo T, Maruyama M, Osada H, Tsujimoto M . Activation of p38 mitogen-activated protein kinase is crucial in osteoclastogenesis induced by tumor necrosis factor. FEBS Lett. 2000; 486(1):23-8. DOI: 10.1016/s0014-5793(00)02231-6. View