ABSTRACT
PURPOSE: To summarize current evidence of the association of bisphosphonate use with breast cancer risk, we used a systematic review and meta-analysis of observational studies to explore this issue. METHODS: A comprehensive search was conducted on PubMed, EMBASE, and the Cochrane Library. Pooled relative risk (RR) estimates and 95% confidence intervals (CIs) were calculated using the random effects model. RESULTS: Bisphosphonate use was associated with a 16% lower breast cancer risk (pool RR0.84, 95%CI 0.77-0.90, n = 8). A protective effect of bisphosphonate was found in cohort studies (RR 0.85, 95%CI 0.80-0.90, n = 4) and case-control studies (RR 0.78, 95%CI 0.64-0.96, n = 4).We also found that the use of bisphosphonate resulted in a statistically significant reduction in all breast cancer risk (RR 0.87, 95%CI 0.81-0.93) and greater reduction in invasive breast cancer risk (RR 0.78, 95%CI 0.68-0.91) and contralateral breast cancer risk (RR, 0.41; 95% CI, 0.20-0.84).With respect to the type of bisphosphonate, we found that alendronate and etidronate resulted significant reduction in breast cancer risk. The short-term use of bisphosphonate (<1 y) led to nonsignificant change (RR 0.93, 95%CI 0.86-1.00), but a significant 26% reduction of breast cancer risk was noted with long-term use (>1 y) (RR 0.74, 95%CI 0.66-0.83). CONCLUSIONS: Our results supported bisphosphonate as being effective in preventing breast cancer, including invasive and contralateral breast cancer. Furthermore, the long-term use (>1 y) of bisphosphonate was more significant in lowering breast cancer risk.
Subject(s)
Bone Density Conservation Agents/therapeutic use , Breast Neoplasms/epidemiology , Diphosphonates/therapeutic use , Administration, Oral , Alendronate/therapeutic use , Breast Neoplasms/prevention & control , Etidronic Acid/therapeutic use , Female , Humans , Risk Assessment , Risk Reduction Behavior , Time Factors , Treatment OutcomeABSTRACT
We previously demonstrated that B1 induced significant cytotoxic effects, cell cycle G1 arrest and apoptosis in human lung cancer A549 cells through the inhibition of DNA topoisomerase II activity. In the present study, we focused on the histone deacetylase (HDAC) modulation of B1 in A549 cells. HDACs, important enzymes affecting epigenetic regulation, play a crucial role in human carcinogenesis. Our findings showed that B1 could suppress the growth of A549 cells in vitro through the inhibition of HDAC activity. Additionally, B1 caused disruption of the mitochondrial membrane potential and induced DNA double-strand breaks (DSBs) in a dose- and time-dependent manner, which consequently led to cell apoptosis. We also observed that B1 inhibited cancer cell migration and angiogenesis-related signal expression, including vascular endothelial growth factor (VEGF) and pro-matrix metalloproteinases-2 and -9 (pro-MMP-2/9). Gelatin zymography suggested that B1 decreased pro-MMP-2 and pro-MMP-9 activity. Transcription factors, signal transducer and activator of transcription 3 (STAT3) and nuclear factor-κB (NF-κB), are vital players in the many steps of carcinogenesis. B1 showed significant dose-response inhibitory effects on cytoplasmic expression and nuclear translocation of both phosphorylated STAT3 (pSTAT3) and NF-κB. It has been well documented that reactivated telomerase confers cancer cells the ability to repair DNA. Real-time PCR results indicated that B1 inhibited STAT3 and NF-κB mRNA expression and telomerase activity. Taken together, our results demonstrated that B1 exerted significant inhibitory effects on HDAC, telomerase activities, oncogenic STAT3 and NF-κB expression. The inhibition of the intricate crosstalk between STAT3 and NF-κB may be a major factor in the molecular action mechanism of B1. The multiple targeting effects of B1 render it a potential new drug for lung cancer therapy.
Subject(s)
Apoptosis/drug effects , Histone Deacetylase Inhibitors/pharmacology , NF-kappa B/metabolism , STAT3 Transcription Factor/metabolism , Signal Transduction/drug effects , Acetylation , Biomarkers , Cell Line, Tumor , Cell Movement/drug effects , DNA Breaks, Double-Stranded/drug effects , Enzyme Precursors/metabolism , Histones/metabolism , Humans , Matrix Metalloproteinase 2/metabolism , Matrix Metalloproteinase 9/metabolism , Membrane Potential, Mitochondrial/drug effects , Phosphorylation , RNA, Messenger/genetics , RNA, Messenger/metabolism , Vascular Endothelial Growth Factor A/metabolismABSTRACT
In our previous studies, we demonstrated that 2,6-bis-(2-chloroacetamido) anthraquinone (B1) showed a highly significant cytotoxic effect. However, its influence in the cell cycle and apoptotic induction effects has not been investigated yet. Here we report the antiproliferative effect of B1, for which IC50 values were 0.57 µmol/l for lung cancer A549 cells, 0.63 µmol/l for colon cancer HT-29 cells, and 0.53 µmol/l for breast cancer MCF-7 cells. DNA topoisomerase II (Topo II), an essential enzyme in DNA synthesis and meiotic division, is highly expressed in cancer cells. Some currently used clinical anticancer drugs (doxorubicin and mitoxantrone) targeting Topo II are very effective antineoplastic agents. B1, sharing the basic structure of known Topo II inhibitors, demonstrated a significant inhibitory effect on Topo II bioactivity. In A549 cells, B1 increased apoptotic cell population with induction of Fas, Bax, and cleaved poly(ADP-ribose) polymerase and by reduction of Bcl-2 expression. Moreover, cell cycle analysis indicated that B1 induced G1 phase arrest through modulation of G1 cell cycle regulatory proteins, such as the downregulation of cyclin D1 and upregulation of Cip/p21, Kip1/p27, and p53. Thus, our study suggests that B1, with the ability to inhibit Topo II activity and cause cell cycle G1 arrest and apoptosis, has potential as a novel anticancer agent.
