Anticancer potential of Salvia miltiorrhiza and its tanshinones: an efficacy perspective

Figures & data

Figure 1 Structure of Danshen tanshinones, their likely botanical synthesis pathway, and select synthetic derivatives.

Notes: (A) Chemical structures of major tanshinones, tanshindiols, and tanshinlactones. (B) Botanical relationship among the major tanshinones in Danshen Salvia miltiorrhiza. (C) Reported structurally modified tanshinones.
Abbreviations: ROS, reactive oxygen species; TIIA, tanshinone IIA.

Figure 2 Tanshinone IIA pharmacokinetic study in mice.

Notes: (A) Concentration–time profile of TIIA in mouse plasma after gavage administration of 75 mg TIIA/kg body weight (mean ± SD, n=5). Liquid chromatography–tandem mass spectrometry method was used for quantitation. (B) Pharmacokinetic parameters of TIIA in mice. Values are mean ± SD (n=5).
Abbreviations: TIIA, tanshinone IIA; SD, standard deviation; AUC, area under the curve; t_max, time to peak concentration; C_max, peak concentration; T_1/2, time for concentration to decrease by half.

Table 1 Summary of in vivo efficacy studies in preclinical animal models of cancer

Tanshinone	Route/frequency	Dose, range	Vehicle	Cancer model	Efficacy
TIIA	Gavage/daily	20 mg/kg	Corn oil	Colo205 colon Ca xenograft	Yes^Citation46
TIIA (plus 5F)	Gavage/twice per week	20 mg/kg	Corn oil	Colo205 colon Ca xenograft	Yes^Citation47
TIIA	Gavage/daily	25 mg/kg	Corn oil	LNCaP prostate Ca xenograft	Yes^Citation48
TIIA	Gavage/every other day	20, 60 mg/kg	Corn oil	MDA-MB-231 breast Ca xenograft	Yes^Citation49
TIIA	Gavage/daily	20, 80 mg/kg	ND	Liver metastasis of SW480 colon Ca	Yes^Citation50
TIIA	Gavage/daily	150, 450, 1,350 mg/kg	ND	Lung metastasis of HepG2 xenograft	Yes^Citation51
TIIA	Gavage/daily	100 mg/kg	Saline	HSV-tk and WT B16 cells(1:9) murine melanoma	No^Citation52
TIIA	ip/4 times per week	30 mg/kg	1% Tween 20/ethanol	MDA-MB-231 and MCF-7 breast Ca xenograft	Yes^Citation53
TIIA	ip/4 times per week	30 mg/kg	ND	MDA-MB-231 and MCF-7 breast Ca xenograft	Yes^Citation54
TIIA	ip/3 times per week	10–40 mg/kg	ND	MCF-7M (CSC) breast Ca xenograft	Yes^Citation42
TIIA	ip/daily	50 mg/kg	Saline	MDA-MB-231 breast Ca xenograft	Yes^Citation41
TIIA	ip/every other day	30 mg/kg	ND	HPV+ Ca Ski cervical Ca xenograft	Yes^Citation44
TIIA	ip/3 times per week	10, 20, 40 mg/kg	ND	GBMS (CSC) glioma xenograft	Yes^Citation55
TIIA	ip/twice per week	30 mg/kg	Corn oil	J5 Liver HCC xenograft	Yes^Citation56
TIIA	ip/every other day	20, 40 mg/kg	0.5% CMC	Ascitic-type hepatic Ca H22 allograft	Yes^Citation57
TIIA	ip/every other day	20 mg/kg	ND	A549 lung Ca xenografts	Yes^Citation58
TIIA	ip/daily	0.3 mg/kg	TPA-CM	CL1-5 lung Ca xenograft and metastases	No59
TIIA	ip/daily	15 mg/kg	Saline	S180 sarcoma xenograft	Yes^Citation60
STS	ip/daily	0.2-50 mg/kg	ND	Lewis lung Ca allograft	No^Citation61
STS	ip/daily	~50 mg/kg	Aqueous injectable	HCCLM3 liver cancer metastasis	Yes^Citation62
ATA	ip/3 times per week	30 mg/kg	ND	MDA-MB-435 melanoma Ca xenograft	Yes^Citation63
ATA	ip/3 times per week	35 mg/kg	ND	MDA-MB-435 melanoma Ca xenograft	Yes^Citation64
TIIA	iv/daily	0.5–2 mg/kg	Nanoparticle	Murine hepatoma allograft	Yes^Citation33
TIIA	iv/every other day	1 mg/kg	Nanoparticle	Murine hepatoma allograft	Yes^Citation35
TIIA	iv/daily–1 week only	0.5–2 mg/kg	ND	Murine C26 colorectal Ca allograft	Yes^Citation65
TIIA	sc/3 times per week	30 mg/kg	0.5% CMC	Breast IDC F35 xenotransplant	Yes^Citation66
TIIA	sc/daily	10, 30 mg/kg	0.5% CMC	MKN45, SGC7901 gastric Ca xenograft	Yes^Citation67
TIIA	sc/every other day	60, 90 mg/kg	Corn oil	LNCaP prostate Ca xenograft	Yes^Citation43
CT	Gavage/daily	150 mg/kg	0.1% SDS	MCF-7 breast Ca xenograft	Yes^Citation68
CT	ip/every other day	2.5 mg/kg	3% DMSO, 30% PEG	HCT116 colorectal Ca xenograft	Yes^Citation69
CT	ip/every other day	5, 25 mg/kg	Corn oil	22Rv1 prostate Ca xenograft	Yes^Citation70
CT	ip/every other day	25 mg/kg	ND (corn oil^a)	22Rv1 prostate Ca metastasis	Yes^Citation71
CT	ip/every other day	10 mg/kg	2% Tween 80	PC-3 prostate Ca xenograft	Yes^Citation72
CT	sc/daily, near tumor	100 mg/kg	ND	Human lung cancer PDX^b	Yes^Citation45
TI	Gavage/daily	150 mg/kg	Corn oil	DU145 prostate Ca xenograft	Yes^Citation73
TI	Gavage/daily	80, 200 mg/kg	Corn oil	H1299 lung Ca xenograft	Yes^Citation74
TI	ip/daily	10 mg/kg	ND	Lung metastasis/MDA- MB-231 breast Ca	Yes^Citation75
TI	ip/daily	0.3 mg/kg	TPA-CM	CL1-5 lung Ca xenograft and metastases	Yes^Citation59
TI	ip/3 times per week	1 mg/kg	CM	Transgenic lung Ca allograft	Yes^Citation76
DH-TI	ip/3 times per week	10 mg/kg	DMSO	MDA-MB-231 breast Ca xenograft	Yes^Citation77
DH-TI	ip before radiation	10 mg/kg	<0.5% DMSO	HeLa cervical Ca xenograft	Yes^Citation78
DH-TI	ip/3 times per week	10 mg/kg	Liposome	AGS gastric Ca xenograft	Yes^Citation79
Tanshinone Mix	iv/daily	2–8 mg/kg	Microemulsion	H22 murine hepatoma allograft	Yes^Citation37
TIIA	ip/daily	24 mg/kg	Corn oil	Rat benign prostatic hyperplasia	Yes^Citation80
TIIA	Gavage/daily	~60–75 mg/kg	Corn oil	TRAMP mouse carcinogenesis (current study)	No

Notes:

a Likely corn oil per other report from same group.⁷⁰

b Patient-derived xenograft in athymic nude mice.

Abbreviations: TIIA, tanshinone IIA; ND, not described; ip, intraperitoneal; CMC, carboxyl methyl cellulose; TPA-CM, tetradecanoyl phorbol acetate conditioned medium; STS, sodium tanshinone TIIA sulfonate; ATA, acetyl tanshinone IIA; iv, intravenous; sc, subcutaneous; CT, cryptotanshinone; SDS, sodium dodecyl sulfate; DMSO, dimethyl sulfoxide; PEG, polyethylene glycol; TI, tanshinone I; CM, conditioned medium; DH-TI, dihydrotanshinone I.

Table 2 Gavage administration of 1.5 mg TIIA/mouse (~60–75 mg/kg) daily did not decrease TRAMP prostate weights or NE-Ca burden by 28 weeks

Group	Genotype of the mice	Gavage began at 8 weeks of age	Number of mice sacrificed by 28 weeks of age	Final body weight (g)^a	Prostate weight (mg)^a	Number of NE-Ca	Total NE-Ca burden (g)^b
1	TRAMP	Vehicle – corn oil	19	26.8±2.31	150±29	4 (20%)	19.4
2	TRAMP	TIIA, 1.5 mg/mouse	20	27.4±2.2	161±38	5 (25%)	19.9
3	Wild type	Vehicle – corn oil	10	27.3± 1.7	78±13	0	–
4	Wild type	TIIA, 1.5 mg/mouse	5	28.4± 1.5	79±18	0	–

Notes:

a Mean ± SD.

b Summation of individual tumor weights of each group.

Abbreviations: TIIA, tanshinone IIA; TRAMP, transgenic adenocarcinoma of mouse prostate; NE-Ca, neuroendocrine-carcinoma; SD, standard deviation.

Figure 3 Summary of reported cellular and molecular effects of tanshinones in cell culture models related to cancer or its microenvironments.

Notes: Arrows indicate induction effects, and block T (⊥) indicates suppression effects. Upward arrow indicates upregulation or activation, and downward arrow indicates downregulation or inactivation. Adapted from Zhang Y, Jiang P, Ye M, Kim SH, Jiang C, Lu J. Tanshinones: sources, pharmacokinetics and anti-cancer activities. International Journal of Molecular Sciences. 2012;13(10):13621–13666.¹⁷
Abbreviations: CT, cryptotanshinone; TIIA, tanshinone IIA; TI, tanshinone I; DH-TI, dihydrotanshinone I; ROS, reactive oxygen species; CSC, cancer stem cells.

Table 3 Cancer-related clinical studies of TIIA and Danshen-containing formulas

Tanshinone tested/tanshinone-containing formula-	Cancers	Treatment(s)	Number of patients	Clinical benefit	References
TIIA	Leukemia	TIIA (30 mg, po, twice per day for 3 months)	Single-case report	CR	90
TIIA	Leukemia	TIIA (80 mg, iv once per day for 54 days)	Single-case report	CR	91
Fufang (composite) Danshen Dripping Pills	Gastric carcinoma	Control: chemotherapy only; treatment: chemotherapy plus Fufang Danshen Dripping Pill (250 mg, po 3 times per day for 3 weeks)	Control: 44 Treatment: 46	CR + PR rate (control vs treatment): 36.4% vs 41.3% (P>0.05) CR + PR + SD rate 43.2% vs 67.4% (P<0.05)	92
Fufang (composite) Danshen Dripping Pills	Colorectal carcinoma	Control: chemotherapy only; treatment: chemotherapy plus Fufang Danshen Dripping Pill (250 mg, po 3 times per day for 3 weeks)	Control: 46 Treatment: 47	CR + PR rate (control vs treatment): 41.3% vs 51.1% (P>0.05) CR + PR + SD rate 58.7% vs 80.8% (P<0.05)	93
Fufang (composite) Danshen Dripping Pills	Esophageal carcinoma	Control: chemotherapy only; treatment: chemotherapy plus Fufang Danshen Dripping Pill (250 mg, po 3 times per day for 3 weeks)	Control: 34	CR + PR rate (control vs treatment): 38.2% vs 52.8% (P>0.05)	94
			Treatment: 36	CR + PR + SD rate 52.9% vs 80.6% (P<0.05)
Fufang (composite) Danshen Dripping Pills	Pancreatic carcinoma	Control: chemotherapy only; treatment: chemotherapy plus Fufang Danshen Dripping Pill (250 mg, po 3 times per day for 2 weeks)	Control: 40	CR +PR rate (control vs treatment): 35.0% vs 46.3% (P>0.05)	95
			Treatment: 41	CR + PR + SD rate 50.0% vs 73.2% (P<0.05)
Fufang (composite) Danshen Dripping Pills	Liver carcinoma	Control: chemotherapy only; treatment: chemotherapy plus Fufang Danshen Dripping Pill (250 mg, po 3 times per day for 3 weeks)	Control: 47	CR + PR rate (control vs treatment): 61.7% vs 69.4% (P>0.05)	96
			Treatment: 49	CR + PR + SD rate 70.2% vs 89.8% (P<0.05)
Fufang (composite) Danshen Dripping Pills	Non-small-cell lung carcinoma	Control: chemotherapy only; treatment: chemotherapy plus Fufang Danshen Dripping Pill (250 mg, po 3 times per day for 2 weeks)	Control: 43 Treatment: 45	CR + PR rate (control vs treatment): 34.9% vs 46.7% (P>0.05) CR + PR + SD rate 62.8% vs 84.4% (P<0.05)	97
Fufang (composite) Danshen injection	Leukemia	Control: chemotherapy only; treatment: chemotherapy plus Fufang Danshen Injection (20-30 mL, iv, once per day for 28 days)	Control: 46 Treatment: 86	Fufang Danshen slightly increased CR rate but significantly attenuated the side effects of chemotherapy	98
Fufang (composite) 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 weeks)	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)	99
Fufang (composite) Danshen injection	Liver carcinoma	Control: TACE only; treatment: TACE plus Fufang Danshen Injection (16 mL, iv once per day for 7 days)	Control: 37 Treatment: 53	1-, 2-, and 3-year survival rate (control vs treatment): 73.0% vs 79.3% (P>0.05), 43.2% vs 66.0% (P<0.05) and 24.3% vs 45.3% (P<0.05)	100

Abbreviations: TIIA, tanshinone IIA; TCM, Traditional Chinese Medicine; po, oral administration; CR, complete remission; iv, intravenous; PR, partial remission; SD, stable disease; TUV, trans-umbilical-portal vein; TACE, transcatheter arterial chemoembolization.

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