A cannabinoid 2 receptor agonist attenuates bone cancer-induced pain and bone loss (original) (raw)
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Bone Pain in Cancer Patients: Mechanisms and Current Treatment
International Journal of Molecular Sciences
The skeletal system is the third most common site for cancer metastases, surpassed only by the lungs and liver. Many tumors, especially those of the breast, prostate, lungs, and kidneys, have a strong predilection to metastasize to bone, which causes pain, hypercalcemia, pathological skeletal fractures, compression of the spinal cord or other nervous structures, decreased mobility, and increased mortality. Metastatic cancer-induced bone pain (CIBP) is a type of chronic pain with unique and complex pathophysiology characterized by nociceptive and neuropathic components. Its treatment should be multimodal (pharmacological and non-pharmacological), including causal anticancer and symptomatic analgesic treatment to improve quality of life (QoL). The aim of this paper is to discuss the mechanisms involved in the occurrence and persistence of cancer-associated bone pain and to review the treatment methods recommended by experts in clinical practice. The final part of the paper reviews exp...
Bone Cancer Pain: From Model to Mechanism to Therapy
Journal of Pain and Symptom Management, 2005
Pain is the cancer-related event that is most disruptive to the cancer patient's quality of life. Although bone cancer pain is one of the most severe and common of the chronic pains that accompany breast, prostate, and lung cancers, relatively little is known about the mechanisms that generate and maintain this pain. Recently, we developed a mouse model of bone cancer pain. Ten days following tumor implantation into the intramedullary space of the femur, significant bone destruction and bone cancer pain-related behaviors were observed and progressed in severity over time. A critical question is how closely this model mirrors human bone cancer pain. In a recent publication, we show that, as in humans, pain-related behaviors are diminished by systemic morphine administration in a dosedependent fashion that is naloxone-reversible. Humans suffering from bone cancer pain generally require significantly higher doses of morphine as compared to individuals with inflammatory pain and in the mouse model the doses of morphine required to block bone cancer pain-related behaviors were 10 times that required to block peak inflammatory pain behaviors of comparable magnitude induced by hindpaw injection of complete Freund's adjuvant (CFA; 1-3 mg/kg). As these animals were treated acutely, there was not time for morphine tolerance to develop and the rightward shift in analgesic efficacy observed in bone cancer pain versus inflammatory pain suggests a fundamental difference in the underlying mechanisms that generate bone cancer versus inflammatory pain. These results indicate that this model will be useful in defining drug therapies that are targeted for complex bone cancer pain syndromes.
Scientific Reports, 2017
Pain is a severe and debilitating complication of metastatic bone cancer. Current analgesics do not provide sufficient pain relief for all patients, creating a great need for new treatment options. The Src kinase, a non-receptor protein tyrosine kinase, is implicated in processes involved in cancer-induced bone pain, including cancer growth, osteoclastic bone degradation and nociceptive signalling. Here we investigate the role of dasatinib, an oral Src kinase family and Bcr-Abl tyrosine kinase inhibitor, in an animal model of cancer-induced bone pain. Daily administration of dasatinib (15 mg/kg, p.o.) from day 7 after inoculation of MRMT-1 mammary carcinoma cells significantly attenuated movement-evoked and non-evoked pain behaviour in cancer-bearing rats. Radiographic-and microcomputed tomographic analyses showed significantly higher relative bone density and considerably preserved bone microarchitecture in the dasatinib treated groups, suggesting a bone-preserving effect. This was supported by a significant reduction of serum TRACP 5b levels in cancer-bearing rats treated with 15 mg/kg dasatinib. Furthermore, immunoblotting of lumbar spinal segments showed an increased activation of Src but not the NMDA receptor subunit 2B. These findings support a role of dasatinib as a disease modifying drug in pain pathologies characterized by increased osteoclast activity, such as bone metastases. Pain is a common, feared and serious complication of cancer occurring in more than 70% of patients with advanced stage cancer 1-3. Bone cancer most often arises when cancerous cells from a primary tumour e.g. breast, prostate or lung metastasize to the bone 4. In the clinic, patients with cancer-induced bone pain describe the pain as heterogeneous and gradually increasing with disease progression 5. Current treatment options include non-steroidal inflammatory drugs (NSAIDS), opioids and antiresorptive agents such as bisphosphonates 1, 6. Although opioids have a key role in pain management, opioids are associated with the development of tolerance, thereby increasing the required dose, leading to severe adverse effects, including nausea, dizziness, constipation, respiratory depression, sedation as well as the risk of addiction 6. Other treatment options include radiotherapy or radioisotopes 7. Radiotherapy has proven to be one of the most efficient treatments for relieving pain in patients suffering from uncomplicated bone metastases. Up to 60% of patients receiving treatment report significant pain relief and 25% experience complete pain relief 7. However, there is a need for improved treatment options and the mechanisms underlying cancer-induced bone pain is still not fully understood. Cancer-induced bone pain contains components of both neuropathic and inflammatory pain but also has its own distinctive characteristics making it a unique pain state 8, 9. When the tumour grows in the bone it damages the surrounding nerves and tissue; produces a wide range of cytokines and growth factors; stimulates
Annals of the New York Academy of Sciences, 2010
In the United States, cancer is the second most common cause of death and it is expected that about 562,340 Americans will have died of cancer in 2009. Bone cancer pain is common in patients with advanced breast, prostate, and lung cancer as these tumors have a remarkable affinity to metastasize to bone. Once tumors metastasize to bone, they are a major cause of morbidity and mortality as the tumor induces significant skeletal remodeling, fractures, pain, and anemia. Currently, the factors that drive cancer pain are poorly understood. However, several recently introduced models of bone cancer pain, which closely mirror the human condition, are providing insight into the mechanisms that drive bone cancer pain and guide the development of mechanismbased therapies to treat the cancer pain. Several of these mechanism-based therapies have now entered human clinical trials. If successful, these therapies have the potential to significantly enlarge the repertoire of modalities that can be used to treat bone cancer pain and improve the quality of life, functional status, and survival of patients with bone cancer.
New targets, new drugs for metastatic bone pain: a new philosophy
Expert Opinion on Emerging Drugs, 2011
Bone pain is a common symptom in bone metastases. The therapies that are currently available include nonsteroidal anti-inflammatory drugs (NSAIDs), opioids, steroids and gabapentin which have been demonstrated to improve neuropathic pain. In addition, preclinical studies indicate that agents such as transient receptor potential vanilloid 1 antagonists and cannabinoid 2 receptor agonist could be considered as adjuncts in ameliorating opioid side effects. New drugs are in the clinical phase of development, among which the most promising molecules seem to be anti-nerve growth factor (NGF) antibodies. Anti-NGF antibody therapy may be particularly effective in blocking bone cancer pain because NGF appears to be integrally involved in the upregulation, sensitization and disinhibition of multiple neurotransmitters, ion channels and receptors in the primary afferent nerve. The best way to treat bone metastases pain is to improve the control of skeletal disease burden. Recently, denosumab, a noncytotoxic IgG2 monoclonal antibody with high affinity for human RANKL, has been demonstrated to significantly prevent clinically relevant increase in pain compared with zoledronic acid across the tumor types. Based on these data, it has been suggested that denosumab has the potential to become a new standard of treatment in bone metastases management.
Challenges in cancer pain management–bone pain
European Journal of Cancer, 2008
Palliative care Cancer-induced bone pain Cancer pain A B S T R A C T Whilst not strictly a neuropathic injury, cancer-induced bone pain (CIBP) is a unique state with features of neuropathy and inflammation. Recent work has demonstrated that osteoclasts damage peripheral nerves (peptidergic C fibres and SNS) within trabeculated bone leading to deafferentation. In addition, glia cell activation and neuronal hyperexcitability within the dorsal horn, are all similar to a neuropathy. Gabapentin and carbamazepine (both anti-convulsants that modulate neuropathy) are effective at attenuating dorsal horn neuronal excitability and normalizing pain-like behaviours in a rat model of CIBP. However alterations in neuroreceptors in the dorsal horn do not mimic neuropathy, rather only dynorphin is upregulated, glia cells are active and hypertrophic and c-fos expression is increased post-noxious behavioural stimulus.
Dichotomic effects of clinically used drugs on tumor growth, bone remodeling and pain management
Scientific Reports, 2019
Improvements in the survival of breast cancer patients have led to the emergence of bone health and pain management as key aspects of patient's quality of life. Here, we used a female rat MRMT-1 model of breast cancer-induced bone pain to compare the effects of three drugs used clinically morphine, nabilone and zoledronate on tumor progression, bone remodeling and pain relief. We found that chronic morphine reduced the mechanical hypersensitivity induced by the proliferation of the luminal B aggressive breast cancer cells in the tumor-bearing femur and prevented spinal neuronal and astrocyte activation. Using MTT cell viability assay and MRI coupled to 18 FDG PET imaging followed by ex vivo 3D µCT, we further demonstrated that morphine did not directly exert tumor growth promoting or inhibiting effects on MRMT-1 cancer cells but induced detrimental effects on bone healing by disturbing the balance between bone formation and breakdown. In sharp contrast, both the FDA-approved bisphosphonate zoledronate and the synthetic cannabinoid nabilone prescribed as antiemetics to patients receiving chemotherapy were effective in limiting the osteolytic bone destruction, thus preserving the bone architecture. The protective effect of nabilone on bone metabolism was further accompanied by a direct inhibition of tumor growth. As opposed to zoledronate, nabilone was however not able to manage bone tumor-induced pain and reactive gliosis. Altogether, our results revealed that morphine, nabilone and zoledronate exert disparate effects on tumor growth, bone metabolism and pain control. These findings also support the use of nabilone as an adjuvant therapy for bone metastases.
Clinical Cancer Research, 2006
Bone cancer pain is a devastating manifestation of metastatic cancer. Unfortunately, current therapies can be ineffective, and when they are effective, the duration of the patient's survival typically exceeds the duration of pain relief. New, mechanistically based therapies are desperately needed. Study of experimental animal models has provided insight into the mechanisms that drive bone cancer pain and provides an opportunity for developing targeted therapies. Mechanisms that drive bone cancer pain include tumor-directed osteoclast-mediated osteolysis, tumor cells themselves, tumor-induced nerve injury, stimulation of transient receptor potential vanilloid type 1 ion channel, endothelin A, and host cell production of nerve growth factor. Current and future therapies include external beam radiation, osteoclast-targeted inhibiting agents, anti-inflammatory drugs, transient receptor potential vanilloid type 1 antagonists, and antibody therapies that target nerve growth factor or ...
Use of Animal Models in Understanding Cancer-induced Bone Pain
Cancer Growth and Metastasis, 2015
Many common cancers have a propensity to metastasize to bone. Although malignancies often go undetected in their native tissues, bone metastases produce excruciating pain that severely compromises patient quality of life. Cancer-induced bone pain (CIBP) is poorly managed with existing medications, and its multifaceted etiology remains to be fully elucidated. Novel analgesic targets arise as more is learned about this complex and distinct pain state. Over the past two decades, multiple animal models have been developed to study CIBP's unique pathology and identify therapeutic targets. Here, we review animal models of CIBP and the mechanistic insights gained as these models evolve. Findings from immunocompromised and immunocompetent host systems are discussed separately to highlight the effect of model choice on outcome. Gaining an understanding of the unique neuromolecular profile of cancer pain through the use of appropriate animal models will aid in the development of more effe...