Advances in plant-based inhibitors of P-glycoprotein

Figures & data

Table 1. Three classifications of P-gp inhibitors.

Generations	Examples	Limitations
First-generation inhibitors	Verapamil, nifedipin, cyclosporin A, ibuprofen, reserpine, tamoxifen amiodarone	These compounds have inherent pharmacological activities, non-specificity and low affinity.
Second-generation inhibitors	Valspodar, dexverapamil, MM36, cinchonine and quinine homodimer Q2	Inhibition of two or more ABC transporters leads to complicated drug–drug interactions by this class of compounds.
Third-generation inhibitors	Tariquidar (XR9576), zosuquidar (LY335979), elacridar (GF120918) and PGP4008	These compounds can inhibit P-gp with high specificity and selectivity. However, comprehensive clinical trials are warranted.

Figure 1. Predicted secondary structure of P-gp and different mechanisms of P-gp inhibition. TMD – transmembrane domain; TM – membrane spanning; NBD – nucleotide binding domains; the ATP sites are rectangles; the three black lines represent glycosylation sites.

Table 2. P-gp expression in different organs.

Organ	Site of expression	Reference
Liver	Biliary canalicular front of hepatocytes.	43
Pancreas	Apical surface of the epithelial cells of small ductules.	44
Kidney	Proximal tubules and mesangial cells.	45
Colon and jejunum	Apical superficial columnar epithelial cells.	46
Adrenal gland	Surface of cells in both the cortex and medulla.	47
Brain	Apical membrane of choroid plexus epithelial cells.	48

Figure 2. The structure of flavonoids that can inhibit P-gp. A: the basic flavonoids structure.

Table 3. An overview of flavonoid inhibitors from in vitro studies.

Compound	P-gp inhibition	Cell line	Reference
1	IC50 = 3.2 μg/mL	HK-2	67
2	IC50 = 6.0 μg/mL	HK-2	67
3	At 30 μM, IC50 = 1667 ± 240 nM	KB-V1	68
4	At 10-50 μM	LS 180	69
5	At 200 μM	MCF-7	70
6	At 30 μM, IC50 = 1233 ± 202 nM	KB-V1	68
7	At 15 μM, IC50 = 0.238 ± 0.085 μM	HepG2/ADR	71
8	At 10–30 μM	MCF-7/ADR	72
9	At 100 μM, IC50 = 0.80 ± 0.20 μM	MDA435/LCC6MDR1	73
10	At 100 μM, IC50 = 8.74 ± 5.88 μM	MDA435/LCC6MDR1	73
11	At 30 μmol/L	HL-60	74

IC₅₀= the concentration required to achieve 50% inhibition of cell growth; HK-2 = human proximal tubule cell line; KB-V1 = human cervical carcinoma cell line; LS 180 = human colon adenocarcinoma cell line; MCF-7 = human breast cancer cell lines; HepG2/ADR = human hepatocellular carcinoma/adriamycin cell line; MCF-7/ADR = doxorubicin resistant breast cancer cell line; MDA435/LCC6MDR1 = human breast cancer cell line; HL-60 = human leukemia cell line.

Figure 3. The structure of alkaloids that can inhibit P-gp. B: the basic alkaloids structure.

Table 4. An overview of alkaloid inhibitors from in vitro studies.

Compound	P-gp inhibition	Cell line	Reference
12	Adriamycin + 25 μM 12, IC50 = 8.86 ± 0.08 μg/mL	MCF-7/ADR	86
13	Doxorubicin + 10 μM 13, IC50 = 0.35 ± 0.03 μg	Caco-2	87
		Doxorubicin + 10 μM 13, IC50 = 19.70 ± 3.91 μM		CEM ADR5000
14	IC50 = 6.6 μg/ml	KB-V1^+	88
15	At 2–5 μM	K562	89
16	IC50 = 27.68 ± 1.04 μM	MCF-7	90
17	At 3 μM	HCT15	91
18	At 3 μM	HCT15	91
19	At 10*10^−3 M	K562/R10	92
20	IC50 = 0.17 μM	KB-V1	93
21	IC50 = 0.17 μM	KB-V1	93
22	Vinblastine + 5 μM 22, IC50 > 2 M	KB-V1	94

IC₅₀= the concentration required to achieve 50% inhibition of cell growth; MCF-7/ADR = doxorubicin resistant breast cancer cell line; Caco-2 = human colonic cancer cells; CEM ADR5000 = P-gp over-expressing sub-line of CCRF-CEM; KB-V1⁺= MDR human epidermoid carcinoma assessed in the presence of vinblastine (1 μg/mL); K562 = human chronic myelogenous leukemia cell line; MCF-7 = human breast cancer cell line; HCT15 = colorectal cancer cell line; K562/R10 = human leukemia cell line; KB-V1 = human cervical carcinoma cell line.

Figure 4. The structure of coumarins that can inhibit P-gp. C: the basic coumarins structure.

Table 5. An overview of coumarin inhibitors from in vitro studies.

Compound	P-gp inhibition	Cell line	Reference
23	IC50 = 10 μM	MDCK-MDR1	102
		IC50 = 43.47 ± 0.27 μM	KB/VCR	103
24	At 10 μM	K562/R7	104
25	At 94 μM	L5178	105
26	IC50 = 5.6 μg/mL	MCF7/ADR	106
27	At 0.5 μg/mL	MCF7/ADR	106
28	IC50 = 2–5 nM	K562/D1-9	107

IC₅₀= the concentration required to achieve 50% inhibition of cell growth; MDCK-MDR1 = MDR1-transfected Madin–Darby canine kidney cells; KB/VCR = long-term exposure of the parental sensitive KB human oral epidermoid carcinoma cell line to vincristine (VCR); K562/R7 = it was obtained by prolonged exposure of the human erythroleukemic cell line (K562) cells to doxorubicin; L5178 = the mouse lymphoma cells; MCF-7/ADR = doxorubicin resistant breast cancer cell line; K562/D1–9 = it was obtained by prolonged exposure of the human erythroleukemic cell line (K562) cells to daunorubicin.

Figure 5. The structure of terpenoids that can inhibit P-gp. D: the basic terpenoids structure.

Table 6. An overview of terpenoid inhibitors from in vitro studies.

Compound	P-gp inhibition	Cell line	Reference(s)
29	IC50 = 167 ± 8 μM	LLC-GA5-COL150	111
30	IC50 = 172 ± 9 μM	LLC-GA5-COL150	111
31	IC50 = 80.8 ± 5.0 μM	LLC-GA5-COL150	111
32	At 20 μM, FAR = 12.1	L5178 Y	112,113
				At 60 μM, FAR = 72.9
33	At 20 μM, FAR = 23.1	L5178 Y	112,113
				At 60 μM, FAR = 82.2
34	At 5 μM	K562/R7	114
35	At 40 μg/mL, FAR = 40.3	L5178 Y	115
36	At 40 μg/mL, FAR = 30.7	L5178 Y	115
37	ED50 = 0.028 μg/mL	MES-SA/DX5	116
		ED50 = 0.0011 μg/mL		HCT 15

LLC-GA5-COL150 = the cells were established by transfection of human MDR1 cDNA encoding P-gp into LLC-PK1 derived from porcine kidney; FAR = fluorescence activity ratio, the values were calculated by (MDR treated/MDR control)/(parental treated/parental control); L5178 Y = the human MDR1 gene-transfected mouse lymphoma cells; K562/R7 = it was obtained by prolonged exposure of the human erythroleukemic cell line (K562) cells to doxorubicin; ED₅₀= the concentration required to achieve 50% effect of cell growth; MES-SA/DX5 = human MDR uterine sarcoma cell line; HCT15 = colorectal cancer cell line.

Figure 6. The structure of saponins that can inhibit P-gp. E: the basic saponins structure.

Table 7. An overview of steride inhibitors from in vitro studies.

Compounds	P-gp inhibition	Cell lines	Reference
38	IC50 = 4.10 ± 0.49 μM	MCF-7/ADR	124
		IC50 = 9.54 ± 1.02 μM		MCF-7
39	At 5–40 μM	KBV20C	125
40	IC50 = 188 μM	AML-2/D100	126
		IC50 = 137 μM		AML-2/D × 100
41	At 10 μM	K562/R7	127
42	At 10 μM	K562/R7	127
43	At 10 μM	K562/R7	127

IC₅₀= the concentration required to achieve 50% inhibition of cell growth; MCF-7 = human breast adenocarcinoma cell line; MCF-7/ADR = doxorubicin resistant breast cancer cell line; KBV20C = MDR human fibroblast carcinoma; AML-2/D100 = the daunorubicin-resistant acute myelogenous leukemia; AML-2/D × 100 = the doxorubicin-resistant AML-2 subline; K562/R7 = it was obtained by prolonged exposure of the human erythroleukemic cell line (K562) cells to doxorubicin.

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