Suppressive Effects of Plumbagin on Invasion and Migration of Breast Cancer Cells via the Inhibition of STAT3 Signaling and Down-regulation of Inflammatory Cytokine Expressions

Abstract

and bone tissues are the most frequent sites for metastases. Up to 70% of patients with metastatic breast cancer develop bone metastases that induce increased osteoclast activity, resulting in local bone destruction and skeletal complications, including pain, hypercalcemia, and nerve compression (1-3). The development and outgrowth of these secondary lesions rely upon the Wei Yan et al. www.boneresearch.org | Bone Research 363intricate cellular and molecular interactions between mammary tumor cells in the bone microenvironment. Tumor cells secrete signaling proteins, such as parathyroid hormone-related peptide (PTHrP) (4), to promote the secretion of RANKL, the receptor activator of nuclear factor-κB ligand, in osteoblast cells that activates bone osteolysis induced by osteoclasts. The concomitant bone destruction releases various growth factors, including transforming growth factor-β (TGF-β) and insulin-like growth factor-1 (IGF-1), to further bind the receptors on the surface of tumor cells and enhance cell proliferation and PTHrP production through activation of the Smad/ MAPK signaling transduction pathways, thus establishing a vicious cycle of bone metastases (5). The most widely used treatments in skeletal complications of varied neoplastic diseases are bisphosphonates (BPs) that block osteoclast activity; this application has been effective in decreasing formation of bone lesions, although this strategy fails to induce the bone regeneration (6). Furthermore, a growing number of case reports have demonstrated that long-term BP therapy might lead to osteonecrosis of the jaw (ONJ) (7-10). Therefore, the search for treatment options that can effectively inhibit tumor growth and reduce bone destruction caused by tumor metastases with mitigated side effects is of pivotal significance.Plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone), derived from the roots of the medical plant plumbago zeylanica, is one of the most investigated compounds. Recent studies have reported the antibacterial effects (11), anti-inflammatory effects (12), and anticancer activities of plumbagin both in vitro (13) and in vivo (14)(15). Previous studies have shown that plumbagin can inhibit tumor cell proliferation in vitro by inducing apoptosis and autophagy of breast neoplasm cells (13) and the invasion of prostate cancer cells (14). Recent studies have also demonstrated that plumbagin can inhibits osteoclastogenesis and reduces human breast cancerinduced osteolytic bone metastasis (16-18), however, more in vivo evidence need to be supplemented and the relevant mechanisms still remain to be investigated. Therefore, the aim of this study is to investigate whether there are any suppressive effects of plumbagin on the invasion and migration of human breast cancer MDA-MB-231SArfp cells and to explore potential functional mechanisms. We thus established an animal model of breast cancer bone metastases via injection of breast cancer cells intracardially. A non-invasive small animal monitoring system in addition to X-ray imaging and histologica...

Plumbagin, a natural naphthoquinone, inhibits the growth of esophageal squamous cell carcinoma cells through inactivation of STAT3

“…Targeting STAT3 signaling represents an important molecular mechanism for the anticancer activity of plumbagin in melanoma (18), gastric cancer (17), breast cancer (8), and prostate cancer (25). In line with these studies, the present data demonstrated that plumbagin treatment significantly suppressed STAT3 activation in EScc cells.…”

“…Plumbagin exhibits multiple biological properties, including antibacterial (5), antimalarial (6), anti-inflammatory (7), and antitumor (8) activities. It has been documented that plumbagin inhibits the invasion of breast cancer cells by inactivating signal transducer and activator of transcription 3 (STAT3) signaling (8). Likewise, plumbagin has been demonstrated to target the STAT3 pathway to block the growth of pancreatic cancer cells (9).…”

Synergistic suppression of human breast cancer cells by combination of plumbagin and zoledronic acid In vitro

“…Greater inhibition of cell migration was observed when tumor cells were treated with a combination of PL and ZA, indicating that PL is able to reinforce the suppressive effect of ZA. Previous studies have revealed that both PL and ZA alone can be effective in inhibiting cell metastasis [29,44] , and our results demonstrate that the combination of PL and ZA exhibited greater efficacy in inhibiting breast cancer metastasis compared with either PL or ZA alone.…”

“…Our previous studies have indicated that PL can effectively attenuate the proliferation of breast cancer cells and concomitant osteoclast formation in the bone microenvironment [28] . Moreover, the PL-mediated inhibition of migration and invasion in breast cancer cells has been confirmed through the suppression of the signal transducer and activator of transcription 3 (STAT3) signaling pathway and the production of inflammatory cytokines [29] . Other researchers have suggested that PL impedes tumor cell proliferation, induces apoptosis and decreases cell metastasis [30] .…”

Plumbagin induces apoptosis in human osteosarcoma through ROS generation, endoplasmic reticulum stress and mitochondrial apoptosis pathway

“…Plumbagin demonstrates its anti-metastatic effects through migration and invasion inhibition in breast cancer (24). Moreover, plumbagin inhibits osteolytic bone metastasis by modulating the tumor-bone microenvironment in breast cancer (25,26).…”