title: A Novel Bufalin Derivative Exhibited Stronger Apoptosis-Inducing Effect than Bufalin in A549 Lung Cancer Cells and Lower Acute Toxicity in Mice.
abstract: BF211 is a synthetic molecule derived from bufalin (BF). The apoptosis-inducing effect of BF211 was stronger than that of BF while the acute toxicity of BF211 was much lower than that of BF. BF211 exhibited promising concentration-dependent anti-cancer effects in nude mice inoculated with A549 cells in vivo. The growth of A549 tumor xenografts was almost totally blocked by treatment with BF211 at 6 mg/kg. Notably, BF and BF211 exhibited differences in their binding affinity and kinetics to recombinant proteins of the α subunits of Na+/K+-ATPase. Furthermore, there was a difference in the effects of BF or BF211 on inhibiting the activity of porcine cortex Na+/K+-ATPase and in their time-dependent effects on intracellular Ca2+ levels in A549 cells. The time-dependent effects of BF or BF211 on the activation of Src, which was mediated by the Na+/K+-ATPase signalosome, in A549 cells were also different. Both BF and BF211 could induce apoptosis-related cascades, such as activation of caspase-3 and the cleavage of PARP (poly ADP-ribose polymerase) in A549 cells, in a concentration-dependent manner; however, the effects of BF211 on apoptosis-related cascades was stronger than that of BF. The results of the present study supported the importance of binding to the Na+/K+-ATPase α subunits in the mechanism of cardiac steroids and also suggested the possibility of developing new cardiac steroids with a stronger anti-cancer activity and lower toxicity as new anti-cancer agents.
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P.R. China.
authors.forename: Miao
authors.initials: M
authors.lastname: Liu
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P.R. China.
authors.forename: Li-Xing
authors.initials: LX
authors.lastname: Feng
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P.R. China.
authors.forename: Peng
authors.initials: P
authors.lastname: Sun
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P.R. China.
authors.forename: Wang
authors.initials: W
authors.lastname: Liu
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P.R. China.
authors.forename: Wan-Ying
authors.initials: WY
authors.lastname: Wu
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P.R. China.
authors.forename: Bao-Hong
authors.initials: BH
authors.lastname: Jiang
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P.R. China.
authors.forename: Min
authors.initials: M
authors.lastname: Yang
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P.R. China.
authors.forename: Li-Hong
authors.initials: LH
authors.lastname: Hu
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P.R. China.
authors.forename: De-An
authors.initials: DA
authors.lastname: Guo
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P.R. China.
authors.forename: Xuan
authors.initials: X
authors.lastname: Liu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects*; D002018:Bufanolides / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D007928:Lethal Dose 50; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011485:Protein Binding; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D013552:Swine; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C000621538:BF211 compound; D002018:Bufanolides; D010879:Piperazines; D011065:Poly(ADP-ribose) Polymerases; D019061:src-Family Kinases; D000254:Sodium-Potassium-Exchanging ATPase; D002118:Calcium