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.
Highlights
Breast cancer is the most common female cancer worldwide and the second leading cause of cancer-related death in women [1, 2]
Studies on the pathological processes that occur at the metastatic bone sites have led to the development of two effective drugs for treatment of bone metastasis; zoledronate (Zol), a third-generation bisphosphonate, and denosumab (Den), a fully human anti-receptor activator of nuclear factor kappa-B ligand (RANKL) antibody [1, 25]
Antiresorptive drugs have revolutionized the treatment and outcome in patients with bone metastases [26], where they decrease the incidence of skeletal complications and are considered the standard of care for reducing SREs in patients with bone metastasis [5]
Summary
Breast cancer is the most common female cancer worldwide and the second leading cause of cancer-related death in women [1, 2]. Bone metastasis is a debilitating aspect of breast cancer that occurs in 75 to 85% of women diagnosed with metastatic breast cancer [2, 3]. Bone metastases are frequently associated with complications, such as hypercalcemia because of osteolysis, nerve compression, intractable bone pain, and pathological fractures ( known as skeletal-related events [SREs]) [4]; these complications can result in morbidity and complex demands on the health care resources. Breast cancer cells secrete factors that act on the pre-osteoclasts, osteoblasts, and bone stromal cells to stimulate the production of mature osteoclasts, which degrade the bone, resulting in the release of growth factors that stimulate breast cancer cell proliferation and perpetuate a vicious osteolytic cycle [6]. Antiresorptive therapy, bisphosphonates (zoledronic acid), and the anti-receptor activator of nuclear factor kappa-B ligand (RANKL) antibody (denosumab) are standard of care to target osteoclast hyperactivity and prevent SREs [7]
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