Saikosaponin D: review on the antitumour effects, toxicity and pharmacokinetics

Figures & data

Figure 1. Chemical structure of SSD.

Table 1. Antitumour effects of SSD in vitro.

Cancer type	Cancer cells	Concn.	Suggested mechanism	Ref.
Hepatoma	SMMC-7721	3.2–19.2 µM	Inhibition of p-STAT3/HIF-1α pathway and further suppression of COX-2 expression. Inhibition of proliferation	(He et al. 2014)
	SMMC-7721, HepG2	3.2–19.2 µM	Inhibition of p-STAT3 /C/EBPβ pathway and further suppression of COX-2 expression. Inhibition of proliferation. Induction of apoptosis.	(Ren et al. 2019)
	HepG2, Hep3B	1–10 µM	Activation of p53 and further activation of Fas/FasL pathway. Inhibition of NF-κB pathway. Induction of G1-cell cycle arrest. Inhibition of proliferation. Induction of apoptosis.	(Hsu, Kuo, Chiang, et al. 2004)
	HepG2	10 µM	Suppression of NF-κB activation. Inhibition of proliferation, angiogenesis and invasion. Induction of apoptosis.	(Wong, Zhang, et al. 2013)
	SMMC-7721	1.28, 3.84 µM	Activation of the p53 pathway. Increase of G0/G1 arrest. Induction of G2/M-phase arrest under hypoxia. Induction of apoptosis. Inhibition of growth. Radiosensitization.	(Wang et al. 2013, 2014)
	SMMC-7721, MHCC97L	3.84 µM	Suppression of mTOR pathway. Inhibition of proliferation. Induction of autophagy formation. Radiosensitization.	(Tian et al. 2019)
	Hep3B	2–15 µM	Upregulation of SENP5 expression and subsequent inhibition of Gli1 SUMOylation. Inhibition of SHh pathway. Inhibition of viability, invasion and migration. Induction of apoptosis. Chemosensitization (HSVtk/GCV).	(Zhang et al. 2019)
Pancreatic cancer	BxPC3	1–8 µM	Activation of MKK4-JNK pathway. Inhibition of proliferation. Induction of apoptosis.	(Lai et al. 2020)
Lung cancer	A549	1–20 µM	Activation of p53 pathway and Fas/FasL apoptotic system. Induction of G1-phase arrest. Induction of apoptosis. Inhibition of proliferation.	(Hsu, Kuo, et al. 2004)
	A549, H1299	5–20 µM	Inhibition of STAT3 pathway. Induction of the G0/G1-phase arrest. Inhibition of proliferation. Induction of apoptosis.	(Wu et al. 2020)
	HCC827, H1975, PC-9, HCC827/GR	5–40 µM	Inhibition of STAT3 pathway. Inhibition of proliferation. Induction of apoptosis. Chemosensitization (gefitinib).	(Tang et al. 2019)
	A549	2 µM	Induction of ROS accumulation. Enhancement of apoptosis. Chemosensitization (CDDP)	( Wang, Zheng, et al. 2010)
Breast cancer	HCC1937	13–100 µM	Inhibition of Wnt/β-catenin pathway. Inhibition of proliferation. Induction of apoptosis.	(Wang et al. 2018)
	MDA-MB-231	6–15 µM	Activation of the p38 pathway. Inhibition of viability. Induction of apoptosis.	(Fu et al. 2020)
	MCF-7	10 µM	Inhibition of SERCA. Activation of the CaMKKβ-AMPK-mTOR signalling cascade, ER stress and UPR. Induction of apoptosis and autophagy.	(Wong, Li, et al. 2013)
	MCF-7/ADR, MCF-7	0.13–0.6 µM	Downregulation of MDR1/P-gp. Reversal of MDR without toxic effect. Chemosensitization (ADR)	(Li, Guan, et al. 2017)
	MCF-7/ADR	0.13–0.6 µM	Inhibition of P-gp expression. Reversal of MDR without toxic effect. Chemosensitization (doxorubicin)	(Li, Xue, et al. 2017)
Ovarian cancer	SKOV3	2 µM	Induction of intracellular ROS accumulation. Enhancement of apoptosis. Chemosensitization (CDDP).	(Wang, Zheng, et al. 2010)
	A2780s, A2780cp, Hey, SKOV3	1, 2 µM	Increase of Ca^2+concentration. Induction of MMP loss. Activation of CaMKI. Inhibition of PPM1D. Promotion of mitochondrial fission. Induction of G2/M arrest. Chemosensitization (CDDP).	(Tsuyoshi et al. 2017)
Cervical cancer	HeLa	10 µM	Inhibition of SERCA. Activation of CaMKK-AMPK-mTOR kinase signalling cascade, ER stress and UPR. Induction of apoptosis and autophagy.	(Wong, Li, et al. 2013)
	HeLa	10 µM	Inhibition of NF-κB pathway and its target oncogenic genes expression. Inhibition of proliferation, angiogenesis and invasion. Induction of apoptosis. Chemosensitization (TNF-α)	(Wong, Zhang, et al. 2013)
	HeLa, Siha	2 µM	Induction of intracellular ROS accumulation. Enhancement of apoptosis. Chemosensitization (CDDP).	(Wang, Zheng, et al. 2010)
Renal cancer	769-P, 786-O	10–20 µM	Inhibition of EGFR/p38 pathway. Upregulation of p53. Induction of apoptosis. Induction of G0/G1-phase arrest. Inhibition of proliferation.	(Cai et al. 2017)
Prostate cancer	DU145	2.5–50 µM	Upregulation of p53. Inhibition of proliferation. Induction of G0/G1-phase arrest. Induction of apoptosis.	(Yao et al. 2014)
	DU145, CWR22Rv1	5, 10 µM	Inhibition of GSK3β/β-catenin pathway in CWR22Rv1. Suppression of proliferation, metastasis and invasion.	(Zhong et al. 2016)
Glioma	U87	1–8 µM	Downregulation of PI3K/Akt and ERK pathway. Activation of JNK. Inhibition of proliferation. Enhancement of apoptosis.	(Li, Cai, et al. 2017)
	C6	2.8–128 µM	Induction of differentiation. Inhibition of growth.	(Tsai et al. 2002)
Osteosarcoma	143B, MG-63	80 µM	Activation of the p53 pathway. Induction of apoptosis. Induction of G0/G1-phase arrest. Inhibition of proliferation.	(Gao et al. 2019)
	U2	5–20 µM	Inhibition of Akt and ERK pathway. Inhibition of proliferation, invasion, and migration. Induction of apoptosis.	(Zhao et al. 2019)
Thyroid carcinoma	ARO, 8305C, SW1736	5–20 µM	Activation of p53 pathway. Inhibition of proliferation. Induction of G1-phase arrest. Induction of apoptosis.	(Liu and Li 2014)
Leukaemia	HL60	12.8–19.2 µM	Upregulation of GR mRNA expression. Induction of G0/G1-phase arrest. Inhibition of proliferation.	(Bu et al. 2000)
Melanoma	A375.S2	5–20 µM	Activation of JNK, p38 and p53. Inhibition of proliferation. Induction of apoptosis.	(Hu et al. 2016)

Table 2. Antitumour effects of SSD in vivo.

Cancer type	Animal models	Concn.	Administration	Duration	Suggested mechanism	Ref.
Hepatoma	HSVtk/Hep3B cells xenograft tumour in nude mice	10 mg/kg	Intraperitoneal injection	Every other day for 33 days	Inhibition of growth. Promotion of apoptosis. Chemosensitization (HSVtk/GCV)	(Zhang et al. 2019)
Lung cancer	HCC827/GR cells xenograft tumour in nude mice	5, 10 mg/kg	Not mentioned	Every day for 14 days	Inhibition of growth. Promotion of apoptosis. Chemosensitization (gefitinib)	(Tang et al. 2019)
Breast cancer	MCF-7/ADR cells xenograft tumour in nude mice	5 mg/kg	Intraperitoneal injection	Every other day for 20 days	Inhibition of growth. Inhibition of P-gp expression. Reversal of MDR without toxic effect.	(Li, Xue et al. 2017)
Thyroid carcinoma	ARO cells xenograft tumour in nude mice	5–20 mg/kg	Oral gavage	Every day for 4 weeks	Inhibition of growth.	(Liu and Li 2014)

Table 3. Toxicity of SSD in vitro/in vivo.

Toxicity	Study type	Models	Dose/Concn.	Administration	Duration	Suggested mechanism	Ref.
Hepatotoxicity	In vitro	LO2 cells	0.4–2 μM	Incubation	24 h	Suppression of PDGF-βR/P38 pathway. Induction of mitochondrial apoptosis.	(Chen et al. 2013)
	In vitro	LO2 cells	0.8–2 μM	Incubation	24 h	Activation of both the death receptor apoptosis pathway and mitochondrial apoptosis pathway.	(Zhang et al. 2016)
	In vivo	ICR mice	300 mg/kg	Oral gavage	Every day for 7 days	Induction of apoptosis and liver injury.	(Zhang et al. 2016)
Neurotoxicity	In vivo	ICR mice	4, 8 mg/kg	Oral gavage	Every day for 7 days	Suppression of Akt/FoxG1 pathway. Inhibition of hippocampal neurogenesis. Impairment of cognitive ability.	(Xu et al. 2018).
	In vitro	Primary neuronal progenitor cells	2, 4 μM	Incubation	24 h	Suppression of GSK3β/β-catenin pathway. Inhibition of proliferation and survival.	(Qin et al. 2019)
	In vivo	C57BL/6J mice	16 mg/kg	Oral gavage	Every day for 14 days	Suppression of GSK3β/β-catenin pathway. Inhibition of cell proliferation and adult neurogenesis. Impairment of cognitive ability.	(Qin et al. 2019)
	In vivo	C57BL/6J mice	16 mg/kg	Oral gavage	Every day for 14 days	Induction of cellular Ca^2+ overload and further disorder of BDNF pathway. Activation of p75NTR cell death signalling. Suppression of TrkB signalling. Inhibition of survival and hippocampal neurogenesis. Induction of cognitive dysfunction.	(Qin et al. 2020)
	In vitro	Cultured murine neocortical neurons	1.28–19.2 μM	Incubation	24 h	Enhancement of cell membrane permeability. Induction of extracellular Ca^2+ influx and cellular Ca^2+ overload. Induction of apoptosis.	(Zheng et al. 2019)
Haemolysis	In vitro	Human erythrocytes	0.64–1.92 μM	Incubation	3 min	Decrease of ATP level in erythrocytes. Change of membrane transport.	(Abe et al. 1978)
	In vitro	Sheep erythrocytes	≥1.28 μM	Incubation	30 min	/	(Nose et al. 1989)
Cardiotoxicity	In vitro	Neonatal rat cardiomyocytes	10 μΜ	Incubation	30 min	Inhibition of SERCA. Blockage of myocardial beating activities	(Wang et al. 2017)

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