Dihydrotanshinone I

Antibacterial activities of cryptotanshinone and dihydrotanshinone I from a medicinal herb, Salvia miltiorrhiza Bunge.[Pubmed: 10664860 ]

Biosci Biotechnol Biochem. 1999 Dec;63(12):2236-9.

Cryptotanshinone and Dihydrotanshinone I, constituents of a medicinal plant, Salvia miltiorrhiza Bunge, had antibacterial activity against a broad range of Gram positive bacteria.
METHODS AND RESULTS:
These compounds generated superoxide radicals in Bacillus subtilis lysates. A recombination-deficient mutant strain of B. subtilis was 2- to 8-fold more sensitive than a wild strain, and this hypersensitivity was reduced in the presence of dithiothreitol as an antioxidant. DNA, RNA, and protein syntheses in B. subtilis were non-selectively inhibited by these compounds.
CONCLUSIONS:
These results suggest that superoxide radicals are important in the antibacterial actions of the agents.

Dihydrotanshinone I inhibits angiogenesis both in vitro and in vivo.[Pubmed: 18180848]

Acta Biochim Biophys Sin (Shanghai). 2008 Jan;40(1):1-6.

Dihydrotanshinone I (DI), a naturally occurring compound extracted from Salvia miltiorrhiza Bunge, has been reported to have cytotoxicity to a variety of tumor cells. In this study, we investigated its anti-angiogenic capacity in human umbilical vein endothelial cells.
METHODS AND RESULTS:
DI induced a potent cytotoxicity to human umbilical vein endothelial cells, with an IC(50) value of approximately 1.28 microg/ml. At 0.25-1 microg/ml, DI dose-dependently suppressed human umbilical vein endothelial cell migration, invasion, and tube formation detected by wound healing, Transwell invasion and Matrigel tube formation assays, respectively. Moreover, DI showed significant in vivo anti-angiogenic activity in chick embryo chorioallantoic membrane assay. DI induced a 61.1% inhibitory rate of microvessel density at 0.2 microg/egg.
CONCLUSIONS:
Taken together, our results showed that DI could inhibit angiogenesis through suppressing endothelial cell proliferation, migration, invasion and tube formation, indicating that DI has a potential to be developed as a novel anti-angiogenic agent.

Combination treatment with dihydrotanshinone I and irradiation enhances apoptotic effects in human cervical cancer by HPV E6 down-regulation and caspases activation.[Pubmed: 22147199 ]

Mol Cell Biochem. 2012 Apr;363(1-2):191-202.

The aim of this study was to investigate the effect of Dihydrotanshinone I (DI) in inhibiting the growth of human cervical cancer cells both in vitro and in vivo, and molecular targets in HeLa cells when treated by DI or irradiation with or without being combined. In this study, MTT, clonogenic assay, flow cytometry, and Western blotting were performed to assess the effect of treatment on cells.
METHODS AND RESULTS:
After treatment with IR, DI, and DI + IR, the apoptosis was 5.8, 13.3 and 22.5% (P < 0.05 vs. control), respectively. Clonogenic assay revealed that the survival of irradiated HeLa cell was significantly reduced by DI treatment. Combination treatment with IR and DI could down-regulate HPV E6 gene expression. Effect of DI on up-regulation of p21 expression and down-regulation of cyclin B1, p34(cdc2) expression in irradiated HeLa cell was concomitant with cell cycle arrest in G(2) phase. The significant increase in caspase-3 activity was also observed in the combination treatment. When HeLa cells were grown as xenografts in nude mice, combination treatment with DI and IR induced a significant decrease in tumor growth, and without signs of general or organ toxicity.
CONCLUSIONS:
These data suggest DI should be tested as the radiosensitizer in vitro and in vivo, which has potential in the treatment of human cervical cancer.

Dihydrotanshinone I induced apoptosis and autophagy through caspase dependent pathway in colon cancer.[Pubmed: 26547530 ]

Phytomedicine. 2015 Nov 15;22(12):1079-87.

Dihydrotanshinone I (DHTS) was previously reported to exhibit the most potent anti-cancer activity among several tanshinones in colon cancer cells. Its cytotoxic action was reactive oxygen species (ROS) dependent but p53 independent. To further study the anti-cancer activity of DHTS and its molecular mechanisms of action in colon cancer both in vitro and in vivo.
METHODS AND RESULTS:
Caspase activity was detected by fluorescence assay. Apoptosis was detected by flow cytometry and TUNEL assay. Protein levels were analyzed by western blotting. Knockdown of target gene was achieved by siRNA transfection. Formation of LC3B puncta and activation of caspase-3 were detected by confocal fluorescence microscope. In vivo anti-colon cancer activity of DHTS was observed in xenograft tumors in NOD/SCID mice. Anti-colon cancer activity of DHTS by inducing apoptosis and autophagy was observed both in vitro and in vivo. Mitochondria mediated caspase dependent pathway was essential in DHTS-induced cytotoxicity. The apoptosis induced by DHTS was suppressed by knockdown of apoptosis inducing factor (AIF), inhibition of caspase-3/9 but was increased after knockdown of caspase-2. Meantime, knockdown of caspase-2, pretreatment with Z-VAD-fmk or NAC (N-Acety-L-Cysteine) efficiently inhibited the autophagy induced by DHTS. A crosstalk between cytochrome c and AIF was also reported.
CONCLUSIONS:
DHTS-induced caspase and ROS dependent apoptosis and autophagy were mediated by mitochondria in colon cancer. DHTS could be a promising leading compound for the development of anti-tumor agent or be developed as an adjuvant drug for colon cancer therapy.

Dihydrotanshinone I Exhibits Strong Inhibition Towards UDP-glucuronosyltransferase (UGT) 1A7.[Reference: WebLink]

Blockade of TNF-α-induced NF-κB signaling pathway and anti-cancer therapeutic response of dihydrotanshinone I.[Pubmed: 26283590]

Acetylcholinesterase complexes with the natural product inhibitors dihydrotanshinone I and territrem B: binding site assignment from inhibitor competition and validation through crystal structure determination.[Pubmed: 24573600]

Cryptotanshinone and dihydrotanshinone I exhibit strong inhibition towards human liver microsome (HLM)-catalyzed propofol glucuronidation.[Pubmed: 23333907]

Fitoterapia. 2013 Mar;85:109-13.

Danshen is one of the most famous herbs in the world, and more and more danshen-prescribed drugs interactions have been reported in recent years. Evaluation of inhibition potential of danshen's major ingredients towards UDP-glucuronosyltransferases (UGTs) will be helpful for understanding detailed mechanisms for danshen-drugs interaction. Therefore, the aim of the present study is to investigate the inhibitory situation of cryptotanshinone and Dihydrotanshinone I towards UGT enzyme-catalyzed propofol glucuronidation.
METHODS AND RESULTS:
In vitro the human liver microsome (HLM) incubation system was used, and the results showed that cryptotanshinone and Dihydrotanshinone I exhibited dose-dependent inhibition towards HLM-catalyzed propofol glucuronidation. Dixon plot and Lineweaver-Burk plot showed that the inhibition type was best fit to competitive inhibition type for both cryptotanshinone and Dihydrotanshinone I. The second plot using the slopes from the Lineweaver-Burk plot versus the concentrations of cryptotanshinone or Dihydrotanshinone I was employed to calculate the inhibition parameters (Ki) to be 0.4 and 1.7μM, respectively. Using the reported maximum plasma concentration (Cmax), the altered in vivo exposure of propofol increased by 10% and 8.2% for the co-administration of Dihydrotanshinone I and cryptotanshinone, respectively.
CONCLUSIONS:
All these results indicated the possible danshen-propofol interaction due to the inhibition of Dihydrotanshinone I and cryptotanshinone towards the glucuronidation reaction of propofol.

J Mol Neurosci. 2014 Jul;53(3):506-10.

Acetylcholinesterase (AChE) is a critical enzyme that regulates neurotransmission by degrading the neurotransmitter acetylcholine in synapses of the nervous system. It is an important target for both therapeutic drugs that treat Alzheimer's disease and organophosphate (OP) chemical warfare agents that cripple the nervous system and cause death through paralysis.
METHODS AND RESULTS:
We are exploring a strategy to design compounds that bind tightly at or near a peripheral or P-site near the mouth of the AChE active site gorge and exclude OPs from the active site while interfering minimally with the passage of acetylcholine. However, to target the AChE P-site, much more information must be gathered about the structure-activity relationships of ligands that bind specifically to the P-site. Here, we review our recent reports on two uncharged, natural product inhibitors of AChE, Dihydrotanshinone I and territrem B, that have relatively high affinities for the enzyme. We describe an inhibitor competition assay and comment on the structures of these inhibitors in complex with recombinant human acetylcholinesterase as determined by X-ray crystallography.
CONCLUSIONS:
Our results reveal that Dihydrotanshinone I binding is specific to only the P-site, while territrem B binding spans the P-site and extends into the acylation or A-site at the base of the gorge.

Int Immunopharmacol. 2015 Sep;28(1):764-72.

The nuclear factor-κB (NF-κB) transcription factors control many physiological processes including inflammation, immunity, apoptosis, and angiogenesis. We identified Dihydrotanshinone I as an inhibitor of NF-κB activation through our research on Salvia miltiorrhiza Bunge.
METHODS AND RESULTS:
In this study, we found that Dihydrotanshinone I significantly inhibited the expression of NF-κB reporter gene induced by TNF-α in a dose-dependent manner. And Dihydrotanshinone I also inhibited TNF-α induced phosphorylation and degradation of IκBα, phosphorylation and nuclear translocation of p65. Furthermore, pretreatment of cells with this compound prevented the TNF-α-induced expression of NF-κB target genes, such as anti-apoptosis (cIAP-1 and FLIP), proliferation (COX-2), invasion (MMP-9), angiogenesis (VEGF), and major inflammatory cytokines (TNF-α, IL-6, and MCP1). We also demonstrated that Dihydrotanshinone I potentiated TNF-α-induced apoptosis. Moreover, Dihydrotanshinone I significantly impaired activation of extracellular signal-regulated kinase 1/2 (ERK1/2), p38 and stress-activated protein kinase/c-Jun NH2-terminal kinase (JNK/SAPK). In vivo studies demonstrated that Dihydrotanshinone I suppressed the growth of HeLa cells in a xenograft tumor model, which could be correlated with its modulation of TNF-α production.
CONCLUSIONS:
Taken together, Dihydrotanshinone I could be a valuable candidate for the intervention of NF-κB-dependent pathological conditions such as inflammation and cancer.

Latin Am. J. Pharm., 2012, 31(7):1060-3.

Inhibition of the activity of UDP-glucuronosyltransferases (UGTs) can induce severe drugdrug interaction and metabolic disorders of endogenous substances. The aim of the present study is to investigate the inhibition of important UGT isoforms by Dihydrotanshinone I, which is an important bioactive component isolated from danshen.
METHODS AND RESULTS:
The nonselective probe substrate 4-methylumbelliferone (4-MU), and the recombinant UGT isoforms were used in the present study. The results showed that 100 M of Dihydrotanshinone I inhibited the activity of UGT1A1, UGT1A3, UGT1A6, UGT1A7, UGT1A8, UGT1A10, and UGT2B7 by 32.7, 61.5, 61.1, 77.5, 47.9, 62.8, and 55.9 %, respectively. Further inhibition kinetic study was performed for the inhibition of UGT1A7 by Dihydrotanshinone I. Dose-dependent inhibition of UGT1A7 by Dihydrotanshinone I was detected, and Dixon and Lineweaver-Burk plots showed that the inhibition of UGT1A7 by Dihydrotanshinone I was best fit to competitive inhibition type. The inhibition kinetic parameter (Ki) was determined to be 2.8 μM. Using the in vivo maximum plasma concentration (Cmax) of Dihydrotanshinone I (11.29 ng/mL, 0.04 μM), the the change of AUC ranged from 0.14 to 1.42 % when the contribution of UGT1A7 towards the metabolism of drugs (fm) ranged from 0.1 to 1.
CONCLUSIONS:
Given that UGT1A7 is one of the most important gastrointestinal UGT isoforms and has high correlation with the occurence of cancer, the potential danshen-drug interaction due to the inhibition of UGT1A7 by Dihydrotanshinone I should be given more attention.

Biological activity of dihydrotanshinone I: effect on apoptosis.[Pubmed: 16232748]

J Biosci Bioeng. 2000;89(3):292-3.

Recently, we have found for the first time that Dihydrotanshinone I, isolated from Salvia miltiorrhiza, exhibited cytotoxicity against various tumor cell lines.
METHODS AND RESULTS:
To investigate whether the mechanism underlying Dihydrotanshinone I toxicity involved apoptosis in cancer cell lines, we examined cell growth arrest and cell death by flow cytometric analysis and DNA fragmentation assay. Dihydrotanshinone I induced cell growth arrest during the S phase and subsequently, apoptosis, following its application to K562/ADR cells, whereas cryptotanshinone did not have these effects.
CONCLUSIONS:
These results suggest that the mode of action of Dihydrotanshinone I involves apoptotic pathways that are different from those involved in cryptotanshinone toxicity.