Dichotomic effects of clinically used drugs on tumor growth, bone remodeling and pain management

Abstract

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 18FDG 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.

CCR2 silencing in sensory neurons blocks bone cancer progression

“…The ipsilateral femurs were removed and postfixed for 48 h in the same solution and then washed in PBS for ex vivo µCT experiments. Scans were performed at the McGill Bone Center using a high-resolution desktop micro-CT scanner, as previously described 61 . Rat femurs were scanned at an X-ray source power of 45 keV/222 µA and at a resolution of 11.25 µm/pixel.…”

CCR2-targeting pepducins reduce T cell-nociceptor interaction driving bone cancer pain

“…Ipsilateral femurs were removed and post-fixated 48 h in the same solution then washed in PBS for ex vivo µCT experiment. Scans were performed at the McGill Bone Center using a high-resolution desktop Micro-CT scanner, as previously described 65 . Rat femurs were scanned at X-ray source power of 45 keV/222 µA and at a resolution of 11.25 µm/pixel.…”

Repurposing Neuroactive Drugs in Oncology: A Mini-Review

“…The anti-tumor effects of opioids are controversial [21], though some studies have reported the ability of opioids to decrease tumor growth. For instance, morphine treatment was found capable of suppressing lung cancer cell proliferation [22], while no effect was seen in breast tumor growth [23], suggesting that morphine treatment may be beneficial in a cancer type-specific manner.…”

“…The analgesics metamizole and paracetamol have been shown to inhibit pancreatic cancer growth [29] while metamizole and acetaminophen exert cytotoxic effects in colon cancer [30]. Synthetic cannabinoids such as nabilone and cannabidiol also show promise as cancer therapeutics [23], yet this remains controversial [31,32].…”