Cathepsin K (CatK) is one of the most potent proteases in lysosomal cysteine proteases family, of which main function is to mediate bone resorption. Currently, CatK is among the most attractive targets for anti-osteoporosis drug development. Although many pharmaceutical companies are working on the development of selective inhibitors for CatK, there is no FDA approved drug till now. Odanacatib (ODN) developed by Merck & Co. is the only CatK inhibitor candidate which demonstrated high therapeutic efficacy in patients with postmenopausal osteoporosis in Phase III clinical trials. Unfortunately, the development of ODN was finally terminated due to the cardio-cerebrovascular adverse effects. Therefore, it arouses concerns on the undesirable CatK inhibition in non-bone sites. It is known that CatK has far-reaching actions throughout various organs besides bone. Many studies have also demonstrated the involvement of CatK in various diseases beyond the musculoskeletal system. This review not only summarized the functional roles of CatK in bone and beyond bone, but also discussed the potential relevance of the CatK action beyond bone to the adverse effects of inhibiting CatK in non-bone sites.
Rheumatoid arthritis (RA) is a chronic inflammatory disorder characterized by progressive bone erosion. Leflunomide is originally developed to suppress inflammation via its metabolite A77 1726 to attenuate bone erosion. However, distinctive responsiveness to Leflunomide is observed among RA individuals. Here we show that Leflunomide exerts immunosuppression but limited efficacy in RA individuals distinguished by higher serum C-reactive protein (CRPHigher, CRPH), whereas the others with satisfactory responsiveness to Leflunomide show lower CRP (CRPLower, CRPL). CRP inhibition decreases bone erosion in arthritic rats. Besides the immunomodulation via A77 1726, Leflunomide itself induces AHR-ARNT interaction to inhibit hepatic CRP production and attenuate bone erosion in CRPL arthritic rats. Nevertheless, high CRP in CRPH rats upregulates HIF1α, which competes with AHR for ARNT association and interferes Leflunomide-AHR-CRP signaling. Hepatocyte-specific HIF1α deletion or a HIF1α inhibitor Acriflavine re-activates Leflunomide-AHR-CRP signaling to inhibit bone erosion. This study presents a precision medicine-based therapeutic strategy for RA.
Mycomedicine is a unique class of natural medicine that has been widely used in Asian countries for thousands of years. Modern mycomedicine consists of fruiting bodies, spores, or other tissues of medicinal fungi, as well as bioactive components extracted from them, including polysaccharides and, triterpenoids, etc. Since the discovery of the famous fungal extract, penicillin, by Alexander Fleming in the late 19th century, researchers have realised the significant antibiotic and other medicinal values of fungal extracts. As medicinal fungi and fungal metabolites can induce apoptosis or autophagy, enhance the immune response, and reduce metastatic potential, several types of mushrooms, such as Ganoderma lucidum and Grifola frondosa, have been extensively investigated, and anti-cancer drugs have been developed from their extracts. Although some studies have highlighted the anti-cancer properties of a single, specific mushroom, only limited reviews have summarised diverse medicinal fungi as mycomedicine. In this review, we not only list the structures and functions of pharmaceutically active components isolated from mycomedicine, but also summarise the mechanisms underlying the potent bioactivities of several representative mushrooms in the Kingdom Fungi against various types of tumour.
Bone metastasis occurs when tumour cells dissociate from primary tumours, enter the circulation (circulating tumour cells, CTCs), and colonize sites in bone (disseminated tumour cells, DTCs). The bone marrow seems to be a particularly dormancy-inducing environment for DTCs, yet the mechanisms of dormancy initiation, reactivation, and interaction within the bone marrow have to be elucidated. Intriguingly, some evidence has suggested that dormancy is a reversible state that is switched ‘on’ or ‘off’ depending on the presence of various bone marrow resident cells, particularly osteoclasts and osteoblasts. It has become clear that these two cells contribute to regulating dormant tumour cells in bone both directly (interaction) and indirectly (secreted factors). The involved mechanisms include TGFβ signalling, the Wnt signalling axis, the Notch2 pathway, etc. There is no detailed review that specifically focuses on ascertaining the dynamic interactions between tumour cell dormancy and bone remodelling. In addition, we highlighted the roles of inflammatory cytokines during this ‘cell-to-cell’ communication. We also discussed the potential clinical relevance of remodelling the bone marrow niche in controlling dormant tumour cells. Understanding the unique role of osteoclasts and osteoblasts in regulating tumour dormancy in bone marrow will provide new insight into preventing and treating tumour bone metastasis.
Gastrointestinal cancers refer to a group of deadly malignancies of the gastrointestinal tract and organs of the digestive system. Over the past decades, considerable amounts of medicinal plants have exhibited potent anticancer effects on different types of gastrointestinal cancers. OMICS, systems biology approaches covering genomics, transcriptomics, proteomics and metabolomics, are broadly applied to comprehensively reflect the molecular profiles in mechanistic studies of medicinal plants. Single- and multi-OMICS approaches facilitate the unravelling of signalling interaction networks and key molecular targets of medicinal plants with anti-gastrointestinal cancer potential. Hence, this review summarizes the applications of various OMICS and advanced bioinformatics approaches in examining therapeutic targets, signalling pathways, and the tumour microenvironment in response to anticancer medicinal plants. Advances and prospects in this field are also discussed.
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Background Pancreatic cancer (PAC), a malignancy that is fatal and commonly diagnosed at a late stage. Despite considerable advancements in cancer treatment, the survival rate of PAC remains largely consistent for the past 60 years. The traditional Chinese medicine formula Pulsatilla Decoction (PD) has been clinically used to treat inflammatory diseases for millennia and recently as a supplementary anti-cancer treatment in China. However, the bioactive ingredients and mechanisms underlying its anti-cancer effect remains unclear. Methods The composition and quality control of PD were verified through analysis by high performance liquid chromatography. Cell viability was determined using Cell Counting Kit-8 assay. The cell cycle distribution was analyzed through PI staining and flow cytometry analysis, while apoptotic cells were measured by double staining with Annexin V-FITC and PI. We used immunoblotting to examine protein expressions. The in vivo effects of β-peltatin and podophyllotoxin were evaluated on a subcutaneously-xenografted BxPC-3 cell nude mice model. Results The current study demonstrated that PD markedly inhibited PAC cell proliferation and triggered their apoptosis. Four herbal PD formula was then disassembled into 15 combinations of herbal ingredients and a cytotoxicity assay showed that the Pulsatillae chinensis exerted the predominant anti-PAC effect. Further investigation indicated that β-peltatin was potently cytotoxic with IC50 of ~ 2 nM. β-peltatin initially arrested PAC cells at G2/M phase, followed by apoptosis induction. Animal study confirmed that β-peltatin significantly suppressed the growth of subcutaneously-implanted BxPC-3 cell xenografts. Importantly, compared to podophyllotoxin that is the parental isomer of β-peltatin but clinically obsoleted due to its severe toxicity, β-peltatin exhibited stronger anti-PAC effect and lower toxicity in mice. Conclusions Our results demonstrate that Pulsatillae chinensis and particularly its bioactive ingredient β-peltatin suppress PAC by triggering cell cycle arrest at G2/M phase and apoptosis.
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