Tanshinones: Sources, Pharmacokinetics and Anti-Cancer Activities
Abstract
:1. Introduction
2. Sources of Tanshinones, Preparative and Analytical Methodologies
2.1. Isolation, Purification and Analytical Methodologies
2.2 Biosynthesis of Tanshinones in S. miltiorrhiza
2.3 Botanical and Alternative Sources of Tanshinones
3. Pharmacokinetics of Tanshinones
3.1. The Pharmacokinetic (PK) Characteristics of Single Administered Agents or as Mixtures
3.2. Structural Modification of Tanshinones
3.3. Improving Pharmacokinetics through Novel Formulations
4. Anti-Cancer Activities of Tanshinones
4.1. Anti-Proliferation and Pro-Apoptosis
4.1.1. Tanshinone I (TI)
4.1.2. Tanshinone IIA (TIIA)
4.1.3. Cryptotanshinone (CT)
4.1.4. Dihydrotanshinone I (DH-TI)
4.2. Pro-Differentiation of Cancer Cells
4.3. Inhibition of Angiogenesis
4.4. Inhibition of Adhesion, Migration, Invasion and Metastasis
4.5. Modulation of Inflammatory and Immune Responses
4.6. Inhibition of Telomerase
4.7. Interaction with DNA Minor Groove and P53 Activation
4.8. Modulation of Androgen Receptor Pathway
4.9. Synergy with Chemotherapy and Radiotherapy
5. Cancer-Related Clinical Studies
6. Novel Tanshinones and Chemical Modifications
7. Summary and Perspective
Acknowledgements
- Conflict of InterestAll authors declare no conflict of interest.
Abbreviations
APL | acute promyelocytic leukemia |
CAM | chicken embryo chorioallantoic membrane |
CCC | countercurrent chromatography |
CD | cyclodextrins |
CPP | copalyl diphosphate |
CR | complete remission |
CT | cryptotanshinone |
DAD | diode array |
DH-TI | dihydrotanshinone I |
DMAPP | dimethylallyldiphosphate |
DXP | 1-deoxy-d-xylulose-5-phosphate |
DXR | 1-deoxy-dxylulose- 5-phosphate reductoisomerase |
DXS | 1-deoxy-d-xylulose-5-phosphate synthase |
ECM | extracellular matrix |
ESI-IT-MS | electrospray ionization quadrupole ion trap mass spectrometry |
FBS | fetal bovine serum |
FPP | farnesyl pyrophosphate |
GA-3P | glyceraldehyde-3-phosphate |
GGPP | geranylgeranyldiphosphate |
GPP | geranyldiphosphate |
HPLC | high-performance liquid chromatography |
HSCCC | high-speed counter-current chromatography |
i.m. | intramuscular |
i.p. | intraperitoneal |
IPP | isopentenyldiphosphate |
i.s.i.p. | in situ intestine perfusion |
i.v. | intravenous |
LC | liquid chromatography |
MEP | 2-C-methyl-d-erythritol-4-phosphate |
MVA | mevalonic acid |
MVD | microvessel density |
p.o. | oral adminstration |
PR | partial remission |
qTOF-MS | quadrupole time-of-flight mass spectrometry |
RIF | Realgar-Indigo naturalis formula |
s.c. | subcutaneous |
SD | stable disease |
SLN | solid lipid nanoparticles |
STS | sodium tanshinone IIA sulfonate |
TI | tanshinone I |
TIIA | tanshinone IIA |
TACE | transcatheter arterial chemoembolization |
TCM | Traditional Chinese Medicine |
TLC | thin-layer chromatography |
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Alternative Source | Characteristics | Products | References |
---|---|---|---|
Callus culture (root, stem, leaf blade, and petiole) | Well established conventional strategy, potential to form a whole plant, and easy maintenance of tissue in culture | Cryptotanshinone, tanshinone I, and tanshinone IIA | [72–75] |
Cell suspension culture | Reliable, sustainable, free of adverse environment factors, automatic control, and scalable for commercial production | Tanshinone I, tanshinone IIA, cryptotanshinone, and ferruginol | [76–79] |
Cell immobilization culture | High cell densities, continuous removal of secreted products, reuse of biocatalysts, and protection for shear-sensitive cells by matrix | Tanshinone IIA, cryptotanshinone, and ferruginol | [80,81] |
Rhizogenesis | Genetic and biosynthetic stability, plant hormone-independent growth, multi-enzyme biosynthetic potential, and relatively low cost | Tanshinone I, tanshinone IIA, tanshinone IIB, tanshinone V, dihydrotanshinone I, cryptotanshinone, tanshinone VI, and diterpene ferruginol | [82–88] |
Crown gall cultures | Fast growth rate, independent of exogenous phytohormones, high productivity of secondary metabolites that are low in normal cell cultures | Cryptotanshinone, tanshinone I, tanshinone IIA, rosmarinic acid, and lithospermic acid B | [89–92] |
Endophytic fungi | Economic, reproducible, ecology-friendly, and easy to scale up | Tanshinone I and tanshinone IIA | [93] |
Species | Administered drug/mixture/extracts (marker compound) | Route | Dose mg/kg | PK for | CA+B, Cmax or Ct (μM) | t1/2β (h) | t1/2γ (h) | References |
---|---|---|---|---|---|---|---|---|
Rat | Danshen extract-lipid emulsion (TIIA) | i.v. | 2 | TIIA | 0.144 (C5min) | 2.27 | [97] | |
4 | TIIA | 0.20 (C5min) | 2.35 | |||||
8 | TIIA | 0.932 (C5min) | 2.17 | |||||
Danshen extract-lipid emulsion (TIIA) Plus polyphenolic extract | i.v. | 2 | TIIA | 0.81 (C5min) | 3.13 | |||
4 | TIIA | 1.17 (C5min) | 3.43 | |||||
8 | TIIA | 22.78 (C5min) | 4.79 | |||||
Rabbit | Danxiongfang formula in Tween80/saline (TIIA) | i.v. | 2.5 | TIIA | 10.99 (CA + CB) | 0.041 | 2.25 | [98] |
Danxiongfang formula Tween80/saline (CT) | i.v. | 4.5 | CT | 15.10 (CA + CB) | 0.039 | 1.42 | ||
Rabbit | CT in Tween80/saline | i.v. | 4.5 | CT | 11.89 (CA + CB) | 0.036 | 1.16 | [99] |
Danxiongfang formula (CT) | i.v. | 4.5 | CT | 15.10 (CA + CB) | 0.039 | 1.42 | ||
Pig | CT in isopropanol solution | i.v. | 10 | CT | 10.44 (CA + CB) | 0.040 | 1.08 | [100] |
TIIA | 2.10 (@tmax = 4.6 min) | 3.15 | ||||||
p.o. | 40 | CT | 0.15 (@1 h) | |||||
i.m. | 20 | CT | 0.19 (@20 min) | |||||
Rat | CT in aqueous solution | i.v. | 20 | CT | 9.57 | 1.06 | [94] | |
CT in aqueous solution | i.p. | 100 | CT | 2.22 (@tmax 1.91 h) (10.6% iv AUC) | 6.88 | |||
CT in aqueous solution | p.o. | 100 | CT | 0.305 (@tmax 5.19 h) (2.1% iv AUC) | 6.64 | |||
Rat | CT as dispersion | p.o. | 20 | CT | 0.085 (@tmax 4 h) | ~4 | [101] | |
TIIA | 0.041 (@tmax 4 h) | ~5 | ||||||
Rat | CT suspension in 1% Tween80 | p.o. | 5.7 | CT | 0.037 (@tmax 0.50 h) | ~0.05 | ~3.9 | [102] |
TIIA | 0.009 (@tmax 0.50 h) | |||||||
Rat | TIIA | p.o. | 15 | TIIA | 18.9 (@tmax 0.85 h) | 0.55 | 3.63 | [95] |
Rat | TIIA in Tween80 suspension | p.o. | 8 | TIIA | 0.012 (@tmax 0.32 h) | 3.84 | [103] | |
CT in Tween80 suspension | p.o. | 5.7 | CT | 0.022 (@tmax 0.56 h) | 2.83 | |||
CT in Tween80 suspension | p.o. | 5.7 | TIIA | 0.012 (@tmax 0.42 h) | 3.12 | |||
Danshen EtOH Extract (TIIA) in Tween80 suspension | p.o. | 8 | TIIA | 0.121 (@tmax 0.64 h) | 5.12 | |||
Danshen EtOH Extract (CT) in Tween80 suspension | p.o. | 5.7 | CT | 0.189 (@tmax 0.58h) | 4.80 | |||
Rat | Tanshinones Mixture (TIIA) | p.o. | 18 | TIIA | 0.06 (@tmax 4h) | [104] | ||
Tanshinones Mixture (CT) | p.o. | 18 | CT | 0.027 (@tmax 4 h) | ||||
Rat | Tanshinones Mixture (TIIA) | p.o. | 4.1 | TIIA | 0.009 (@tmax 0.54 h) | 2.07 | [105] | |
Tanshinones Mixture (CT) | p.o. | 1.91 | CT | 0.002 (@tmax 0.42 h) | 1.13 | |||
Tanshinones Mixture (TI) | p.o. | 1.1 | TI | 0.006 (@tmax 0.42 h) | 3.00 | |||
Tanshinones Mixture (DH-TI) | p.o. | 1.91 | DH-TI | 0.012 (@tmax 0.79 h) | 1.69 | |||
Rat | Tanshinones Mixture (TIIA) | p.o. | 5.79 | TIIA | 0.076(@tmax 0.61 h) | 0.40 | 3.70 | [106] |
Tanshinones Mixture (CT) | p.o. | 9.82 | CT | 0.145 (@tmax 0.86 h) | 0.69 | 2.81 | ||
Tanshinones Mixture (TI) | p.o. | 3.9 | TI | 0.198 (@tmax 0.60 h) | 0.94 | 4.72 | ||
Tanshinones Mixture (DH-TI) | p.o. | 3.58 | DH-TI | 0.041(@tmax 0.74 h) | 0.54 | 3.65 | ||
Rat | Danshen tanshinone extract (TIIA) in CMC 0.5% | p.o. | 20 | TIIA | 0.057 (@tmax 6.67 h) | 7.04 | [107] | |
tanshinone extract + salvianolic acid B extract | p.o. | 20 | TIIA | 0.060 (@tmax 4.35 h) | 5.86 | |||
tanshinone extract + notoginseng extract | p.o. | 20 | TIIA | 0.054 (@tmax 4.33 h) | 6.90 | |||
Tanshinone extract + borneol (Bingpian) | p.o. | 20 | TIIA | 0.066 (@tmax 2.00 h) | 0.032 | 6.28 | ||
All extracts combined | p.o. | 20 | TIIA | 0.075 (@tmax 3.67 h) | 0.041 | 6.02 |
Tanshinone tested/Tanshinone containing formula | Cancers | Treatment(s) | Number of patients | Clinical benefit | References |
---|---|---|---|---|---|
TIIA | Leukemia | TIIA (80 mg, i.v. once per day) | Single case report | CR | [280] |
TIIA | Leukemia | TIIA (30 mg, p.o., twice per day) | Single case report | CR | [279] |
Fufang Danshen Injection | Leukemia | Control: chemotherapy only; Treatment: chemotherapy plus Fufang Danshen Injection (20–30 mL, i.v., once per day) | Control: 46 Treatment: 86 | Fufang Danshen slightly increased CR rate, but significantly attenuate the side effects of chemotherapy. | [281] |
Fufang Danshen Injection | Liver carcinoma | Control: surgical resection only; Treatment: surgical resection plus chemotherapy and Fufang Danshen Injection (250 mL, TUV perfusion, once per day for 7 days, repeat every 3–4 week ) | Control: 30 Treatment: 30 | 1- and 2-year recurrence rates (control vs. treatment): 60.7% vs. 15.3% (p < 0.05) and 75.1% vs. 30.0% (p < 0.05). | [282] |
Fufang Danshen Injection | Liver carcinoma | Control: TACE only; Treatment: TACE plus Fufang Danshen Injection (16 mL, i.v. once per day for 7 days) | Control: 37 Treatment: 53 | 1-, 2- and 3-year survival rate (control vs. treatment): 72.97% vs. 79.25%, 43.24% vs. 66.04% (p < 0.05) and 24.32% vs. 45.28% (p < 0.05). | [283] |
Fufang Danshen Dripping Pill | Pancreatic carcinoma | Control: chemotherapy only; Treatment: chemotherapy plus Fufang Danshen Dripping Pill (250 mg, p.o. 3 times per day) | Control: 40 Treatment: 41 | CR + PR and CR + PR + SD rates (control vs. treatment): 35.0% vs. 46.3% and 50.0% vs. 73.2% (p < 0.05). | [284] |
RIF (formula) | Leukemia | Control: ATRA (30 mg per day) plus placebo for RIF. Treatment: RIF (2.25–7.5 g per day, p.o.) plus placebo for ATRA | Control: 59 (placebo controlled) Treatment: 61 | CR rate (control vs. treatment): 94.9% vs. 96.7% (p > 0.05). | [285] |
RIF (formula) | Leukemia | Alternating treatments with chemotherapy and RIF (6.0–7.5 g per day, p.o. 30 days of a cycle) | Treatment: 62 (no control group) | 3-, 5-, 7- and 10-year relapsefree survival rates: 68.41%, 48.15%, 38.89%, 18.52%, respectively. 3-year and 5 to 10-year survival rates: 88.52% and 86.88%. | [286] |
RIF (formula) | Leukemia | RIF (3.75–9 g per day, p.o.) | Multiple cases reports over many years: n = 18 to 204/report | CR rate: 91.67%-100%. | [287–291] |
© 2012 by the authors; licensee Molecular Diversity Preservation International, Basel, Switzerland. This article is an open-access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).
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Zhang, Y.; Jiang, P.; Ye, M.; Kim, S.-H.; Jiang, C.; Lü, J. Tanshinones: Sources, Pharmacokinetics and Anti-Cancer Activities. Int. J. Mol. Sci. 2012, 13, 13621-13666. https://doi.org/10.3390/ijms131013621
Zhang Y, Jiang P, Ye M, Kim S-H, Jiang C, Lü J. Tanshinones: Sources, Pharmacokinetics and Anti-Cancer Activities. International Journal of Molecular Sciences. 2012; 13(10):13621-13666. https://doi.org/10.3390/ijms131013621
Chicago/Turabian StyleZhang, Yong, Peixin Jiang, Min Ye, Sung-Hoon Kim, Cheng Jiang, and Junxuan Lü. 2012. "Tanshinones: Sources, Pharmacokinetics and Anti-Cancer Activities" International Journal of Molecular Sciences 13, no. 10: 13621-13666. https://doi.org/10.3390/ijms131013621
APA StyleZhang, Y., Jiang, P., Ye, M., Kim, S.-H., Jiang, C., & Lü, J. (2012). Tanshinones: Sources, Pharmacokinetics and Anti-Cancer Activities. International Journal of Molecular Sciences, 13(10), 13621-13666. https://doi.org/10.3390/ijms131013621