Table 2.

FDA approved non-cancer drugs repurposed for cancer treatment analyzed for their interactions with P-glycoprotein.

Drug	Original indication, mechanism	New anticancer indication, mechanism	Mol mass (g/mol)	pKa	LogP	Pgp interactions predicted (see Table 1)	Pgp interactions measured
Metformin	Diabetes Mellitus AMPK ↑a	Breast, adenocarcinoma, prostate, colorectal AMPK ↑, NF-κB ↓, TNF ↓, MCP-1 ↓	129.2	12.3	−0.92	-NR3 No type I/ II units No allocrite No substrate	(130, 131) No substrate
Valproic acid	Antiepileptic GABA ↑	Leukemia, solid tumors HDACI ↓, HDACII ↓, NF-κB ↓, IL-6 ↓	144.2	5.14	2.8	No type I/ II units No allocrite No substrate	(132) No substrate
Aspirin	Analgesic, antipyretic COX-1 ↓, COX-2 ↓	Colorectal cancer Prostate cancer COX-2 ↓, NF-κB ↓, AP-1 ↓	180.2	3.5	1.19	1 type II unit Allocrite/modulator Inducer	(133, 134) (135) Inducerb
Nitroxoline	Antibiotic	Bladder, breast cancer MetAP-2 ↓	190.2	6.88	1.99	No type I/ II units No allocrite	–
Thalidomide	Antiemetic in pregnancy TNF-α ↓	Multiple myeloma NF-κB ↓, STAT3 ↓	258.2	11.59	0.33	-NR3 2 type II units Allocrite/modulator Inducer	(136) Inducerd
Leflunomide	Rhematoid arthritis DHODH ↓	Prostate Cancer PDGFR ↓, EGFR ↓, FGFR ↓, NF-κB ↓	270.2	10.8	2.8	-NR3 Type II unit Allocrite Inducer	(137) Interaction with BCRPc
Zoledronic acid	Anti-bone resorption Osteoclast ↓	Multiple myeloma, prostate cancer, breast cancer CXCR-4 ↓, MMPs ↓, IL-6 ↓, Bcl-2 ↓, Bax ↑, FOXO3α ↑	272.0	0.7, 6.7		No allocrite	–
Celecoxib	Osteoarthritis, rheumatoid arthritis COX-2 ↓	Colorectal cancer, lung cancer COX-2 ↓, NF-κB ↓	381.4	11.1	3.53	-NR3, 1 type I unit Allocrite	(138) Pgp repressionb
Vesnarinone	Cardioprotective	Oral cancer, leukemia, lymphoma NF-κB ↓, IL-8 ↓, VEGF ↓, AP-1 ↓	395.5	2.86		-NR3, 1type I unit Allocrite/modulator	(139) Inhibitore
Statins, e.g., Lovastatin	Myocardial infarction HMG-CoA reductase ↓	Prostate cancer, leukemia NF-κB ↓, HMG-CoA reductase ↓	404.5	4.26	~4	2 type I units Allocrite/modulator	(113) Modulatorf
Noscapine	Antitussive, antimalarial, analgesic Bradykinin ↓	Multiple cancer types NF-κB ↓, HIF-1α ↓, Bcl-2 ↓, p21 ↑, p53 ↑, AIF ↑	413.4	12.86 7.14	2.85	-NR3, 2 type I, 1 type II units Allocrite Inhibitor Inducer	(140) Inhibitor
Wortmannin	Antifungal	Leukemia NF-κB ↓, AP-1 ↓	428.1	–	–	Type I / II units Non-amphiphilic MRP2 substrate	(141) MRP2 substrate
Methotrexate	Acute leukemia DHFR ↓	Osteosarcoma, breast cancer, Hodgkin lymphoma NF-κB ↓, TNF-α ↓	454.2	4.8, 5.5	0.74	-NR3, 2 type I or 1 type II Substrate	(142) Substrateg
Minocycline	Acne	Ovarian cancer, glioma MMPs ↓	457.5 g	–	−0.03	-NR3, 1 type II unit Substrate Inhibitor Inducer	(143) Substrate Inhibitor
Thio-colchicoside	Muscle relaxant GABA ↓	Leukemia, multiple myeloma NF-κB ↓	563.2	12.74	0.34	-NR3, Type I/II units Substrate Inhibitor Inducer	(144)
Rapamycin	Immunosuppressant mTOR ↓	Colorectal cancer, lymphoma, leukemia NF-κB ↓, IL-6 ↓, IKK ↓	914.19	~9	4.3	-NR3, Type I / II units Substrate Inhibitor	(145) Substrate Inhibitor

^aAMPK, AMP-activated protein kinase; AIF, apoptosis-inducing factor; AP-1; Bax, Bcl-2-associated X protein; Bcl-2; BCRP, breast cancer resistance protein; CXCR-4, CXC chemokine receptor-4; DHFR, dihydrofolate reductase; DHODH, dihydroorotate dehydrogenase; FGFR, fibroblast growth factor receptor; FOXO, forkhead homeobox type O; GABA, γ-aminobutyric acid; HIF-1α, hypoxia-inducible factor-1α; HMG-CoA; IKK; MCP-1, monocyte chemoattractant protein-1; MetAP, methionine aminopeptidase; MMP, matrix metalloproteinase; mTOR; NF-κB; p21; p53; VEGF; ↑, upregulation; ↓, downregulation.

^bConflicting data may be due the fact that Aspirin is a Pgp inducer [see also (136)] and possibly may at the same time reduce Pgp expression via COX-2 inhibition. The same is true for celecoxib. Specific COX-2 inhibition may be used as a new therapeutic strategy to prevent seizure-induced P-glycoprotein up-regulation at the blood-brain barrier (138).

^cPgp and BCRP have overlapping substrate specificity (16, 18).

^dTreatment with thalidomide produced a concentration- and time-dependent induction of Pgp expression in rat trophoblasts. By contrast, in human trophoblasts, thalidomide decreased the expression of Pgp in a concentration- and time-dependent manner. The difference of trophoblast behavior between both culture models, i.e., rat and human is also noted in vivo for the teratogenic effect of thalidomide between rat and human.

^eMost allocrites can be inhibitors at high concentrations.

^fP-glycoprotein expressing cells exhibited a collateral sensitivity to lovastatin. Collateral sensitivity occurs when allocrites strongly activates the Pgp ATPase activity and produce ROS, see e.g., Verapamil (112).

^gThus, a deficiency in the methotrexate (MTX) carrier enables Pgp to confer resistance to MTX, suggesting that hydrophilic compounds become Pgp substrates when they enter cells by passive diffusion.

The table is adapted from Gupta et al. (30).