Overcoming P-Glycoprotein-Mediated Multidrug Resistance in Colorectal Cancer: Potential Reversal Agents among Herbal Medicines

Table 1

Summary of herbal medicines as P-gp reversal agents in CRC.

Scientific name	Herbal constituents	Anti-cancer drug	Model	Pharmacological outcome	Reference
Salvia miltiorrhiza	Tanshinone IIA	Digoxin	Caco-2 cells, Rats	Tanshinone IIA inhibited digoxin in P-gp-overexpressing membrane vesicles with an IC (50) of 2.6 microM. P-gp-mediated efflux of TSA into the gut lumen	[19]
	Tanshinone IIB	Digoxin, Vinblastine	CaCo-2 intestinal cells, Rats	At the free plasma concentrations of Tashinone IIB in the range of IC50 values (28.1–37.3 mM), Tashinone IIB effectively inhibited digoxin and vinblastine transport.	[20]
	Tanshinone I, tanshinone IIA, cryptotanshinone, dihydrotanshinone miltirone	Doxorubicin	Caco-2 cells	Cryptotanshinone and dihydrotanshinone increased intracellular accumulation of the P-gp substrate anti-cancer drugs, presumably by downregulating P-gp mRNA and protein levels, and inhibiting P-gp ATPase activity.	[21]
Curcuma longa	Curcumin	Vincristine	HCT-8/VCR in vitro and in vivo	The sensitivity of cells to vincristine, cisplatin, fluorouracil, and hydroxycamptothecin was enhanced by suppressing the expression of the MDR gene and P-gp. The combination of curcumin and VCR in vivo significantly inhibited xenograft growth.	[22]
	Curcumin	Daunorubicin	Caco-2 cells	Decrease in the efflux ratio of daunorubicin by curcuminoids indicates that curcuminoids could modulate the efflux transporters expressed in Caco-2, especially P-gp.	[23]
Sinomenium acutum	Sinomenine	Doxorubicin	MDR-Caco-2 cells	Sinomenine downregulated P-gp expression in MDR-Caco-2 cells and enhanced the sensitivity of MDR-Caco-2 cells towards doxorubicin	[24]
Stephania tetrandra	Tetrandine, fanchinoline	Paclitaxel, Verapamil	P-gp positive HCT15 colon cancer cells	Tetrandine (3.0 microM) and fanchinoline (3.0 microM) enhanced the accumulation of rhodamine 123 in HCT15 cells. Both only affected the accumulation and residual rate of rhodamine 123 in P-gp-positive HCT 15 cells.	[25]
Bufo gargarizans	Cinobufagin	Doxorubicin	P-gp overexpressing LoVo/ADR, HCT116/L, Caco-2/ADR cells	Cinobufagin significantly enhanced the sensitivity of P-gp-overexpressing cells to DOX without affecting the corresponding parental cells.	[26]
Coptis japonica	6-(dioxolo[-g]isoquinoline-5-carbonyl)-2,3-dimethoxy-benzoic acid methyl ester, oxyberberine,; 8-oxo-epiberberine,; 8-oxocoptisine, berberine, palmatine	Paclitaxel	five tumor cell lines in vitro; A549 (nonsmall cell lung adenocarcinoma),; SK-OV-3 (ovarian),; SK-MEL-2 (skin melanoma),; XF498 (CNS) and HCT15 (colon).	8-oxocoptisine was of significant P-gp MDR inhibition activity with ED50 value 0.0005 pg/mL in HCT15 cell.	[27]
Piper nigrum, Piperlongum	Piperine,; Two small piperine analogs(Pip1,2)	Vincristine, Colchicine,; Paclitaxel	Human KB 3–1, KB ChR 8–5, SW480 and HEK 293 cells	Both analogs, co-administered with vincristine, colchicine or paclitaxel were able to reverse the resistance in SW780 (CRC). Accumulation of P-gp substrate, rhodamine 123, in the resistant cells was observed as a result of alteration of the P-gp efflux.	[28]
Hedyotis Diffusa	Standardized ethanol extract Hedyotis Diffusa (EEHDW)	5-FU,; Adriamycin	(i) In vitro: HCT-8 cells; (ii) In vivo: male BALB/c nude mice injected with HCT-8/5-FU cells, HCT-8 cells	EEHDW or combination treatment could markedly downregulate the mRNA and protein expression of ABCC1/MRP1, ABCB1/P-gp, ABCG2/BCRP, Cyclin D1, CDK4 and Bcl-2 and upregulate the mRNA and protein expression of p21 and Bax in a dose-dependent manner in in xenograft tumors.	[29]
Schisandra chinensis	γ-Schisandrin compound	Oxaliplatin	MDR of human carcinoma of colon cell THC-8307/OXA	γ-Schisandrin decreased the expression of P-gp in THC-8307/OXA human colon carcinoma cells.	[30]
Glycyrrhiza glabra	Glabridin	Verapamil	CaCo-2 cells, MDCKII cells, rats	Glabridin is a substrate for P-gp. Low oral bioavailability is due to PgP/MDR1-mediated efflux and first-pass metabolism.	[31]
Glycyrrhiza inflate	Oral administration of decoction	Rhodamine 123	rat jejunum membranes in vitro	G. inflate showed slight inhibition of P-gp function in the intestinal membrane.	[32]
Daphne genkwa	Oral administration of decoction	Rhodamine 123	rat jejunum membranes in vitro	D. genkwa may be a strong inhibitor of P-gp compared to G. inflate.	[32]
Stemona tuberosa Lour	Neotuberostemonine, Neostenine	Rhodamine 123	Caco-2 monolayer model	Both alkaloids were identified to be the substrates of P-gp.	[33]
Andrographis paniculata	Andrographolid (AG)	5-FU, Adriamycin, Cisplatin	HCT-8/5-FU multidrug-resistant colorectal cancer cell line	The reversal modulation of MDR by AG is related to its downregulation of overexpression of P-170. AG might act as a chemosensitizer when co-administered with anticancer drugs.	[34]