Background Bone cancer pain (BCP) remains a clinical challenge due to the limited and side effects of therapeutic methods. Folic acid has been known as an FDA approved dietary supplement and proved to have an analgesic effect in neuropathic pain. Here we investigate the role and mechanism of folic acid in bone cancer pain of a rat model. Methods Walker 256 tumor cells were inoculated into the left tibia of rats to induce bone cancer pain model. Pain reflex were assessed by paw withdrawal threshold (PWT) response to Von Frey filaments and paw withdrawal latency (PWL) response to thermal stimulation. Folic acid was injected intraperitoneally to evaluate its analgesic effect in rats with bone cancer pain. Western blotting and qPCR were used to determine P2X2/3 receptor protein and mRNA levels in ipsilateral L4-6 dorsal root ganglion (DRG) and spinal dorsal horn (SDH). Results The PWT and PWL of rats with bone cancer pain were obviously decreased compared to the naïve and sham rats. Interestingly, continuous folic acid treatment significantly increased the PWT and PWL of rats with bone cancer pain. P2X2 and P2X3 receptors were clearly upregulated at both mRNA and protein expression in L4-6 DRG and SDH of rats with bone cancer pain. P2X2 and P2X3 receptors were mainly localized with CGRP (calcitonin gene-related peptide) or IB4 (isolectin B4) positive neurons in L4-6 DRG of rats with bone cancer pain. Notably, continuous folic acid treatment significantly reduced the expression of P2X2 and P2X3 receptors in L4-6 DRG and SDH of rats with bone cancer pain. Finally, intrathecal injection of A317491 (a selective antagonist of P2X2/3 receptors) markedly elevated the PWT and PWL of rats with bone cancer pain. Conclusion These results suggest that folic acid has an effective antinociceptive effect on bone cancer pain, which is mediated by downregulating P2X2/3 receptors in L4-6 DRG and SDH of rats with bone cancer pain. Folic acid may be a novel therapeutic strategy in cancer patients for pain relief.
Introduction Curcumin (CUR) is a general ingredient of traditional Chinese medicine, which has potential antitumor effects. However, its use clinically has been limited due to its low aqueous solubility and bioavailability. In order to improve the therapeutic effect of CUR on osteosarcoma (i.e., bone cancer), a multifunctional micelle was developed here by combining active bone accumulating ability with tumor CD44 targeting capacity.Methods The CUR loaded micelles were self-assembled by using alendronate-hyaluronic acid-octadecanoic acid (ALN-HA-C18) as an amphiphilic material. The obtained micelles were characterized for size and drug loading. In addition, the in vitro release behavior of CUR was investigated under PBS (pH 5.7) medium containing 1% Tween 80 at 37℃. Furthermore, an hydroxyapatite (the major inorganic component of bone) affinity experiment was studied. In vitro antitumor activity was evaluated. Finally, the anti-tumor efficiency was studied.Results The size and drug loading of the CUR loaded ALN-HA-C18 micelles were about 118 ± 3.6 nm and 6 ± 1.2%, respectively. CUR was released from the ALN-HA-C18 micelles in a sustained manner after 12 h. The hydroxyapatite affinity experiment indicated that CUR loaded ALN-HA-C18 micelles exhibited a high affinity to bone. CUR loaded ALN-HA-C18 micelles exhibited much higher cytotoxic activity against MG-63 cells compared to free CUR. Finally, CUR loaded ALN-HA-C18 micelles effectively delayed anti-tumor growth properties in osteosarcoma bearing mice as compared with free CUR.Conclusion The present study suggested that ALN-HA-C18 is a novel promising micelle for osteosarcoma targeting and delivery of the hydrophobic anticancer drug CUR.
Chen Hanbin,Li Guanghong,Deng Lin,Li Shuli,Huang Songqiang,Lee Simon Ming-Yuen,Nie Xiaowei,Bian Jin-Song
Background Pain serves as a vital protective mechanism triggered by tissue damage. While NSAIDs and opioids offer relief, their prolonged usage is hindered by adverse effects. Developing analgesics with fewer side effects is crucial for effective pain treatment. The TRPV1 channel is a key target for pain relief, with its inhibitors effectively reducing hyperalgesia in animals. This research utilized virtual screening to identify TRPV1-selective natural compounds for potent analgesic properties. Results The physcion exhibited the notable affinity for TRPV1 compared to the compounds examined. After conducting molecular dynamics simulations, physcion emerged as the compound demonstrating the highest binding affinity towards TRPV1, a finding corroborated by calcium imaging, which validated its inhibitory impact. Furthermore, physcion mitigated the stretch number in the acetic acid-induced stretching model, prolonged the latency period in the hot water tail-flick and hot plate assays, and heightened the pain withdrawal threshold lowered by complete Freund’s adjuvant (CFA). Notably, physcion exerted a marked effect in ameliorating bone cancer-induced pain in the hot plate and von Frey tests. Additionally, physcion diminished the levels of inflammatory cytokines and the mRNA expression of both inflammatory and calcium-related genes in the CFA-induced murine model. Furthermore, physcion downregulated the expression of inflammatory genes induced by tumor necrosis factor-α (TNF-α) in RAW264.7 cells. The underlying mechanism potentially involves the suppression of the NF-κB and MAPK signaling cascades. Conclusions Our investigation underscores the potential of physcion as a promising candidate for analgesic therapy.
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