Apoptotic signaling in bufalin‐ and cinobufagin‐treated androgen‐dependent and ‐independent human prostate cancer cells

Abstract

Prostate cancer has its highest incidence in the USA and is becoming a major concern in Asian countries. Bufadienolides are extracts of toxic glands from toads and are used as anticancer agents, mainly on leukemia cells. In the present study, the antiproliferative and apoptotic mechanisms of bufalin and cinobufagin on prostate cancer cells were investigated. Proliferation of LNCaP, DU145, and PC3 cells was measured by 3-(4,5-dimethylthiazol-2-yle)-2,5-diphenyltetrazolium bromide assay and the doubling time (tD) was calculated. Bufalin and cinobufagin caused changes in the tD of three prostate cancer cell lines, which were more significant than that of human mesangial cells. In addition, bufadienolides induced prostate cancer cell apoptosis more significantly than that in breast epithelial cell lines. After treatment, the caspase-3 activity and protein expression of caspase-3, -8, and -9 were elevated. The expression of other apoptotic modulators, including mitochondrial Bax and cytosolic cytochrome c, were also increased. However, expression of p53 was only enhanced in LNCaP P rostate cancer is currently showing its highest incidence for decades, and is the second-leading cause of cancer death among men in the USA.(1) It has been estimated that 186 320 new cases of prostate cancer will be diagnosed and that 28 660 deaths attributed to prostate cancer will occur in the USA in 2008.(2) In addition, the mortality of prostate cancer has also increased in Asian countries during the past decade. An assay for prostate-specific antigen has raised the early detection level of prostate cancer, which is curable by surgical and radiation therapies. Androgen ablation is the most common treatment for metastatic prostate cancer; however, 20-30% patients with prostate cancer experience recurrent disease.(3,4) Therefore, searching for chemoprevention or chemical controls for prostate cancer has become a crucial concern.Bufalin and cinobufagin, the major digoxin-like components of Chan-Su extracts from the venom of Bufo bufo gargarizan, have been reported as Na + -K + -ATPase inhibitors that result in elevation of the intracellular calcium concentration. (5,6) On the basis of this mechanism, bufalin and cinobufagin increase vasoconstriction, and have long been used as a treatment for heart failure by Chinese medicine in Asian countries. Disruption of intracellular calcium homeostasis induces apoptosis in diverse cell types.(7) Our previous results have illustrated that bufalin and cinobufagin are able to induce elevated calcium concentration and cell apoptosis in prostate cancer cells, but the detailed mechanism of this remains unclear.(8) Bufalin is also known as a topoisomerase II inhibitor. Topoisomerase II is a nuclear enzyme that relaxes supercoiled DNA at the time of DNA replication. Its inhibitors result in protein-linked DNA double-strand breaks. (9) Some of the topoisomerase poisons, such as etoposide and adriamycin, are efficient and widely prescribed anticancer drugs. (10) According to the mechanism described above, bu...

Effect of arenobufagin on human pancreatic carcinoma cells

“…Similar to the present findings for arenobufagin, certain studies have reported that bufalin, another representative cardiac glycoside compound from secreted toad toxins, inhibited cell proliferation in various cancer cells and induced apoptosis and cell cycle arrest in PC cells (21,(39)(40)(41). The exact mechanism by which arenobufagin induces apoptosis in pancreatic cells is unclear.…”

Effects of bufalin on the proliferation of human lung cancer cells and its molecular mechanisms of action

“…Bufalin isolated from Chansu was reported to have the activity of inducing apoptosis in cancer cells such as human prostate, hepatocellular, endometrial and ovarian cancer cells and leukemia cells. (Gu et al 2007;Takai et al 2008;Watabe et al 1996;Yu et al 2008). However, whether or not bufalin has inhibitory activity against the proliferation of human NSCLC cells and its molecular mechanisms of action are unclear.…”

Bufalin, a Traditional Oriental Medicine, Induces Apoptosis in Human Cancer Cells

“…These results suggest that bufalin suppress cell proliferation and cause apoptosis in prostate cancer cells via a sequence of apoptotic modulators, including Bax, cytochrome c, and caspases. The upstream mediators might be p53 and Fas in androgen-dependent LNCaP cells and Fas in androgen-independent DU145 and PC3 cells (Yu et al, 2008).…”