Table 4.

Antitumor effects and mechanisms of Chinese Cordyceps in various cancer models.

Cancer	Bioactive Component	Pharmacological Effects	Cell line	Major Mediating Signaling Pathways	Mechanism of Action	Ref.
Bladder cancer
	Cordycepin	↓Migration and invasion	TNF-α-induced 5637 and T-24 cells	NF-κB AP-1	↓MMP-9	[23]
Breast cancer
	Cordycepin	↑Apoptosis	MDA-MB-231 cells	Caspase	↑Bax (mitochondria) ↑Cytochrome c (cytosol) ↑PARP ↑c-caspases-9, -3 ↑DNA fragmentation	[19]
	Cordycepin	↑Autophagy	MCF-7 cells	Autophagy	↑LC3-II ↑Autophagosome-like structure	[19]
	Cordycepin	↑Apoptosis	MDA-MB-435 and T47D cells		↑DNA fragmentation ↑Histone γH2AX ↓RNA synthesis	[26]
	C. militaris extract	↑Apoptosis	MCF-7 cells	Caspase	↑Bax/Bcl-2 ↑c-caspase-7, -8	[25]
	Cordycepin	↑Apoptosis	C6 glioma cells	A2AR Caspase	↑Caspase-7 ↑p-p53 ↑PARP	[110]
Cervical cancer
	Cordycepin	↑Apoptosis ↓Cell cycle	SiHa cells HeLa cells		↓CDK-2 ↓Cyclin-E1 ↓Cyclin-A2 ↑ROS	[111]
	CCP (C. cicadae polysaccharides)	↑Apoptosis ↓Cell cycle	hela cells	Akt	↑Bak ↑Bax ↑Caspase-3, -7, -9 ↓P21 ↓P27 ↓CDK2 ↓Cyclin E1 ↓Cyclin A2 ↓Bcl-2 ↓Bcl-xl ↓PARP	[112]
Colon cancer
	CSP	↑Autophagy, ↑Apoptosis	HCT116 cells	Autophagy mTOR Caspase	↑LC3B-II ↑Caspase-8, -3	[51,65]
	Cordycepin	↓Cell cycle	HCT116 cells	JNK MAPK	↑p21WAF1 ↓Cyclin B1 ↓Cdc25c ↓Cdc2	[24]
Colorectal cancer
	C. militaris extract	↓Cell cycle	RKO cells		↑Bax ↑Bim ↑Bak ↑Bad ↑PARP ↑p-p53 ↑c-caspase -9, -3	[113]
Gastric cancer
	Cordycepin	↑Apoptosis	AGS cells	PI3K/Akt	↑Caspase-9, -3, -7 ↑Bax ↓Bcl-2	[114]
	CECJ (C. jiangxiensis extract)	↑Apoptosis ↓Cell cycle	SGC-7901 cells	Caspase	↑Caspase-3	[115]
Liver cancer
	Adenosine	↑Apoptosis	HepG2 cells	Caspase	↑TNF ↑TRADD ↑TRAIL-R2 ↑FADD ↑Caspase-9, -8, -3	[8]
	Adenosine	↑Apoptosis	BEL-7404 cells	Caspase	↑Caspase-8, -9, -3 ↑c-PARP ↑Bak ↑Mcl1 ↑Bcl-xl	[6]
	Adenosine	↑Apoptosis	HuH-7 Fas-deficient cells	Caspase	↑AMP ↓Caspase-3, -8 ↓c-FLIP	[7]
	CMF (C. militaris extract)	↓Migration and invasion ↓Tumor growth	SMMC-7721 cells	Akt ERK	↓p-VEGFR2 ↓p-Akt ↓p-ERK	[116]
Lung cancer
	AECS1, AECS2 (C. sinensis nucleosides extract)	↓Tumor growth	Lewis xenograft mouse	Akt NF-κB	↓p-Akt ↓MMP2 ↓MMP9 ↓p-IκBα ↓TNF-α ↓COX-2 ↓Bcl2 ↓Bcl-xl ↑Bax	[117]
	CS (C. sinensis extract)	↑Apoptosis	H157 NSCLC cells		↓VEGF ↓bFGF	[118]
	C. militaris extract	↑Apoptosis ↓Cell cycle	NCI-H460 cells		↑P53 ↑P21 ↑53BP1	[119]
Mouse melanoma
	Cordycepin	↓Proliferation	B16-BL6 cells	A3R	↑GSK-3β ↓Cyclin D1 protein	[28]
	CME-1	↓Tumor migration	B16-F10 cells	NF-κB MAPK (ERK and p38)	↓MMP-1	[49]
	EPSP	↓Tumor migration	B16 cells		↓c-Myc ↓c-Fos ↓VEGF	[120]
Myeloma cancer
	Cordycepin	↑Apoptosis	MM.1S cells	Caspase	↑Caspase-9, -3, -8 ↓RNA synthesis	[8]
Oral cancer
	CMP (C. militaris polysaccharides)	↑Apoptosis ↓Cell cycle	4NAOC-1 cells	STAT3 ERK	↓ki-67 ↓EGFR ↓IL-17A ↓Cyclin B1 ↓DNA synthesis	[121]
	WECM (C. militaris extract)	Apoptosis ↓Cell cycle	SCC-4 cells		↓PCNA ↓VEGF ↓Caspase-3 ↓c-fos	[122]
Ovarian cancer
	CME (C. militaris extract)	↑Apoptosis ↓Migration	SKOV-3 cells	NF-κB	↓TNF-1R ↓Bcl-2 ↑Bcl-xl	[123]
		↑Autophagy ↓Tumor growth	A2780 and OVCAR3 cells	ENT1-AMPK-mTOR	↑LC3II/LC3I ↑p-AMPK	[124]
Prostate cancer
	Cordycepin	↓Migration and invasion	LNCaP cells	PI3K/Akt	↑TIMP-1 ↑TIMP-2 ↓MMP-2 ↓MMP-9	[21]
Testicular cancer
	Cordycepin	↑Apoptosis ↓Cell cycle	MA-10 cells	Caspase	↑Caspase-9, -3, -7 ↑DNA fragmentation	[20]

AMP, activated protein kinase; A₂AR, adenine 2A receptor; A₃R, adenine 3 receptor; c-FLIP, cellular FADD-like interleukin-1β-converting enzyme inhibitory protein; c-PARP, cleaved-poly ADP-ribose polymerase; COX-2, cyclooxygenase-2; c-Fos, c-Myc, cellular proto-oncogenes; cyclin B1, Cdc25c and Cdc2, cell cycle regulatory proteins; ERK, extracellular signal-regulated kinases; FADD, fas-associated death domain; JNK, Jun N terminal kinase; LC3-II, the lipidated form of LC3B; MMP, mitochondrial membrane potential; mTOR, mechanistic target of rapamycin; MAPK, mitogen-activated protein kinases; p-Akt, phosphorylated serine/threonine kinase; p21WAF1, cyclin-dependent kinase inhibitor; TNF, tumor necrosis factor; TRADD, TNF receptor-associated death domain; TRAIL-R2, TNF-related apoptosis-inducing ligand receptor 2; VEGF, vascular endothelial growth factor.