Tanshinone IIA activates calcium-dependent apoptosis signaling pathway in human hepatoma cells

Abstract

Tanshinone IIA (Tan IIA), a natural product from herb Salvia miltiorrhiza Bunge, has potential anti-tumor activity. The aim of this study was to pinpoint the molecular mechanisms underlying Tan IIA-induced cancer cell apoptosis. Human hepatoma BEL-7402 cells treated with Tan IIA underwent assessment with MTT assay for cell viability, 10-day culture for colony formation, flow cytometry and fluorescence microscopy for apoptosis and cell cycle analysis. Changes in intracellular [Ca(2+)] and mitochondrial membrane potential (∆ψ) reflected the calcium-dependent apoptosis pathway. RT-PCR was used to detect gene expression of Bad and metallothionein 1A (MT 1A). Cytotoxicity of Tan IIA was tested in human amniotic mesenchymal stem cells (HAMCs). Tan IIA exhibited dose-dependent and time-dependent anticancer effects on BEL-7402 cells through apoptosis and G(0)/G(1) arrest. Cells treated with Tan IIA increased their intracellular calcium, decreased their mitochondrial membrane potential and induced Bad and MT 1A mRNA expression. No adverse effects of Tan IIA were found in HAMCs. In conclusion, these results indicate that Tan IIA-induced cancer cell apoptosis acts via activation of calcium-dependent apoptosis signaling pathways and upregulation of MT 1A expression.

Tanshinones: Sources, Pharmacokinetics and Anti-Cancer Activities

“…As one of the most extensively investigated tanshinones, TIIA’s anti-neoplastic activities have been reported in various cancer cells including prostate [132,133], breast [134–140], colon [141], lung [142–145], liver [146–154], stomach [155–159], pancreas [160], bile duct [161], kidney [162], ovary [163–165], cervix [166], nasopharynx [167,168], glioma [169], osteosarcoma [170] and leukemia [171–175], in a broad concentration range from sub-micromolar to high micromolar. Sub-apoptotic concentrations of TIIA could induce G 0 /G 1 , S or G 2 /M arrest depending upon the cancer cell types.…”

“…The induction of cell cycle arrest was associated with up-regulation of P53, P21 and P27, and down-regulation of cyclinD 1 , CDK2, CDK4, cdc25 and cdc2 [132,141,146,147,150,155,156,162]. Higher concentrations of TIIA could induce caspase-dependent apoptosis, which was generally associated with increases of P53, P21, Fas, TNF-α, Bax/Bcl-2 ratio, disruption of mitochondrial membrane potential (MMP), enhancement of cytochrome c release, decreases of survivin, Mcl-1 L , EGFR and LC3-II, and activation of caspase-8, caspase-9 and caspase-3, suggesting the involvements of both intrinsic (Bax/Bcl-2/MMP/cytochrome c release/caspase-9/caspase3) and extrinsic (Fas/TNF-α/caspase-8/caspase-3) apoptosis pathways [132–137,141–143,146–151,155,162,163,169–171]. TIIA was reported to decrease ErbB-2/HER2/Neu in Colo205 colon cancer xenograft tumors in male severe combined immunodeficient (SCID) mice (20 mg/kg of TIIA in corn oil, oral gavage, once per day for 30 days) [141], but not in MCF-7 and MDA-MD-231 breast cancer xenograft tumors in female nude mice (30 mg/kg of TIIA in Tween 20:ethanol = 1:99, subcutaneous (s.c.) injection, four times per week for four weeks) [137].…”

Tanshinone IIA attenuates the cerebral ischemic injury-induced increase in levels of GFAP and of caspases-3 and -8

“…TSA is able to traverse the blood brain barrier although the brain content is limited to 30% of 5 the plasma concentration (Chen et al, 2007), and this could relate to its effects in reducing the volume of cerebral infarction and maintenance of neuronal function (Lam et al, 2003). TSA has been shown to have protective effects against focal cerebral ischemia/reperfusion (I/R) injury in animal models (Tang et al, 2010; and has been proposed as a potential therapeutic agent in heart disease, liver disease and cancer treatment (Dai et al, 2012). …”

Metallothionein differentially affects the host response to Listeria infection both with and without an additional stress from cold-restraint

“…In addition to the MT level affecting the redox status of cells (Maret 2011;Vašák and Meloni 2011;Torreggiani et al 2013), MT may be affecting cation levels, including Ca 2+ , which directly and indirectly can affect oxidative and ER stress (Dai et al 2012;Hu et al 2013) as well as immunity.…”