Hypericin targets osteoclast and prevents breast cancer-induced bone metastasis via NFATc1 signaling pathway

Abstract

Bone is the most common target organ of metastasis of breast cancers. This produces considerable morbidity due to skeletal-related events, and severely reduces the quality of life. Increased osteoclast activity is implicated in breast cancer outgrowth in the bone microenvironment. Our previous observation of an anti-osteoclastic activity of hypericin, a natural plant compound, led us to investigate whether hypericin could inhibit bone metastasis and osteolysis caused by breast cancer. We find that hypericin inhibited the upregulation of osteoclasts stimulated by breast cancer cells. The activity of hypericin on osteoclasts and breast cancer-mediated osteoclastogenesis was associated with the inhibition of NFATc1 signaling pathway and attenuation of Ca2+ oscillation. Furthermore, hypericin suppresses invasion and migration in breast cancer cells, but has little effect on breast cancer-cell induced RANKL/OPG ratio in osteoblast or the expression of osteoclast-activating factors. Administration of hypericin could reduce tumor burden, osteolysis induced by direct inoculation of MDA-MB-231 cells into the bone marrow cavity of the tibia as well as metastasis of bone and improve survival in an experimental metastasis model by intracardiac injection of MDA-MB-231 breast cancer cells. Taken together, these results suggest that hypericin may be a potential natural agent for preventing and treating bone destruction in patients with bone metastasis due to breast cancer.

Therapeutic effect of palbociclib in chondrosarcoma: implication of cyclin-dependent kinase 4 as a potential target

“…The ability of tumor cells to migrate and invade is the most important factor that contributed to the advanced metastasis of cancer [23]. Since the results from TMA assay indicated that the level of CDK4 was dramatically correlated with the metastasis stage of patients suffered with chondrosarcoma, we therefore investigated the vital significance of CDK4 in the migration and invasion of chondrosarcoma cells in vitro.…”

“…With respect to the evaluation of invasive capability, transwell assay using a culturing chamber precoated with Matrigel (100 g/ml, 100 μl/well) was employed as previously described [23]. Briefly, the top chambers were seeded with CS-1 or SW1353 cells at 3 × 10 3 cells/well with 1 μM palbociclib while the lower chambers were added with 500 μl complete medium containing 10% FBS.…”

Proanthocyanidins-Mediated Nrf2 Activation Ameliorates Glucocorticoid-Induced Oxidative Stress and Mitochondrial Dysfunction in Osteoblasts

“…Several plant-derived antioxidants can activate the Nrf2 pathway and protect cells against oxidative damage [ 21 ]. Proanthocyanidins (PAC) are a group of polyphenolic flavonoids present in many vegetables, flowers, fruits, and nuts [ 22 ] and exhibit antibacterial, antiviral, antioxidant, and other pharmaceutical effects [ 23 ]. In addition, several studies have shown that PAC can activate the Nrf2 pathway [ 24 , 25 ].…”

Hesperetin Prevents Bone Resorption by Inhibiting RANKL-Induced Osteoclastogenesis and Jnk Mediated Irf-3/c-Jun Activation

“…The stimulation of RANKL to mediate the trimerization of RANK, the cell-surface receptor on preosteoclasts, promotes the activation of a series of intracellular molecular responses ( Zhou et al, 2017 ; Ouyang et al, 2018 ). The activation of TRAF-6 initially induces the expression of phosphorylated TAK-1, which leads to the subsequent phosphorylation of IKKα/β, Jnk, Erk, and p38, all of which are vital for osteoclastogenesis.…”