Clinical Perspective of FDA Approved Drugs With P-Glycoprotein Inhibition Activities for Potential Cancer Therapeutics
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) plays a crucial role in determining response against medications, including cancer therapeutics. It is now well established that p-glycoprotein acts as an ATP dependent pump that pumps out small molecules from cells. Ample evidence exist that show p-glycoprotein expression levels correlate with drug efficacy, which suggests the rationale for developing p-glycoprotein inhibitors for treatment against cancer. Preclinical and clinical studies have investigated this possibility, but mostly were limited by substantial toxicities. Repurposing FDA-approved drugs that have p-glycoprotein inhibition activities is therefore a potential alternative approach. In this review, we searched the Drugbank Database (https://www.drugbank.ca/drugs) and identified 98 FDA-approved small molecules that possess p-glycoprotein inhibition properties. Focusing on the small molecules approved with indications against non-cancer diseases, we query the scientific literature for studies that specifically investigate these therapeutics as cancer treatment. In light of this analysis, potential development opportunities will then be thoroughly investigated for future efforts in repositioning of non-cancer p-glycoprotein inhibitors in single use or in combination therapy for clinical oncology treatment.
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Specific inhibitors of MDR1 such as tariquidar have shown limited success in clinic at re-sensitizing MDR1 overexpressing patients to chemotherapy due to toxicities, low drug-drug interactions and inability to achieve desired concentrations of tariquidar in tumors.
“Specific inhibitors of MDR1 such as tariquidar have shown limited success in the clinic at re-sensitizing MDR1 overexpressing patients to chemotherapy due to toxicities, low drug-drug interactions and the inability to achieve desired concentrations of tariquidar in tumors (34).”
From The drug efflux pump MDR1 promotes intrinsic and acquired resistance to PROTACs in cancer cells (2022) · cites this paper as [34]
Small molecule inhibitors of MDR1 have shown limited therapeutic benefit in clinical trials.
“these drugs have shown limited therapeutic benefit”
From The drug efflux pump MDR1 promotes intrinsic and acquired resistance to PROTACs in cancer cells (2022) · cites this paper as [34]
No MDR1 inhibitors are FDA-approved for cancer therapy.
“no MDR1 inhibitors FDA-approved for cancer therapy (34).”
From The drug efflux pump MDR1 promotes intrinsic and acquired resistance to PROTACs in cancer cells (2022) · cites this paper as [34]
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Cites
Cancer drug resistance: an evolving paradigm
Holohan, C., Van Schaeybroeck, S., Longley, D. B., & Johnston, P. G. (2013) · Nature Reviews Cancer · doi:10.1038/nrc3599 · Cited by 4,681 · see citing works
DrugBank: a comprehensive resource for in silico drug discovery and exploration
Wishart, D. S. (2006) · Nucleic Acids Research · doi:10.1093/nar/gkj067 · Cited by 3,892 · see citing works
Targeting multidrug resistance in cancer
Szakács, G., Paterson, J. K., Ludwig, J. A., Booth-Genthe, C., & Gottesman, M. M. (2006) · Nature Reviews Drug Discovery · doi:10.1038/nrd1984 · Cited by 3,609 · see citing works
BIOCHEMICAL, CELLULAR, AND PHARMACOLOGICAL ASPECTS OF THE MULTIDRUG TRANSPORTER
Ambudkar, S. V., Dey, S., Hrycyna, C. A., Ramachandra, M., Pastan, I. H., & Gottesman, M. M. (1999) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pharmtox.39.1.361 · Cited by 2,059 · see citing works
Chen, C.-J., Chin, J. E., Ueda, K., Clark, D. P., Pastan, I., Gottesman, M. M., & Roninson, I. B. (1986) · Cell · doi:10.1016/0092-8674(86)90595-7 · Cited by 1,898 · see citing works
Molecular mechanisms of drug resistance
Longley, D., & Johnston, P. (2005) · The Journal of Pathology · doi:10.1002/path.1706 · Cited by 1,686 · see citing works
Cordon‐Cardo, C., O’Brien, J. P., Boccia, J. P., Casals, D., Bertino, J. R., & Melamed, M. R. (1990) · Journal of Histochemistry & Cytochemistry · doi:10.1177/38.9.1974900 · Cited by 1,062 · see citing works
Thomas, H., & Coley, H. M. (2003) · Cancer Control · doi:10.1177/107327480301000207 · Cited by 931 · see citing works
Active outward transport of daunomycin in resistant ehrlich ascites tumor cells
Danø, K. (1973) · Biochimica et Biophysica Acta (BBA) - Biomembranes · doi:10.1016/0005-2736(73)90191-0 · Cited by 729 · see citing works
Three Decades of P-gp Inhibitors: Skimming Through Several Generations and Scaffolds
Palmeira, A., Sousa, E., Vasconcelos, M. H., & Pinto, M. M. M. (2012) · Current Medicinal Chemistry · doi:10.2174/092986712800167392 · Cited by 492 · see citing works
Kruijtzer, C. M. F., Beijnen, J. H., Rosing, H., Huinink, W. W. T. B., Schot, M. E., Jewell, R. C., Paul, E. M., & Schellens, J. H. M. (2002) · Journal of Clinical Oncology · doi:10.1200/jco.2002.12.116 · Cited by 465 · see citing works
Boesch, D., Gavériaux‐Ruff, C., Jachez, B., et al. (1991) · PubMed · Cited by 364 · see citing works
Tariquidar (XR9576): a P-glycoprotein drug efflux pump inhibitor
Fox, E., & Bates, S. E. (2007) · Expert Review of Anticancer Therapy · doi:10.1586/14737140.7.4.447 · Cited by 350 · see citing works
Tobe, T., Uchino, J., Endo, Y., Oto, M., Okamoto, E., Kojiro, M., Shikata, T., Tanikawa, K., Tsuzuki, T., Mizumoto, R., et al. (1994) · Cancer · doi:10.1002/1097-0142(19941115)74:10 · Cited by 335 · see citing works
Nanayakkara, A. K., Follit, C. A., Chen, G., Williams, N. S., Vogel, P. D., & Wise, J. G. (2018) · Scientific Reports · doi:10.1038/s41598-018-19325-x · Cited by 285 · see citing works
Phase I/II trial of cyclosporine as a chemotherapy-resistance modifier in acute leukemia.
List, A. F., Spier, C. M., Greer, J. P., et al. (1993) · Journal of Clinical Oncology · doi:10.1200/jco.1993.11.9.1652 · Cited by 280 · see citing works
Cripe, L. D., Uno, H., Paietta, E. M., Litzow, M. R., Ketterling, R. P., Bennett, J. M., Rowe, J. M., Lazarus, H. M., Luger, S. M., & Tallman, M. S. (2010) · Blood · doi:10.1182/blood-2010-04-277269 · Cited by 236 · see citing works
Greenberg, P. L., Lee, S. J., Advani, R. H., Tallman, M. S., Sikic, B. I., Letendre, L., Dugan, K., Lum, B. L., Chin, D. L., Dewald, G. W., et al. (2004) · Journal of Clinical Oncology · doi:10.1200/jco.2004.07.048 · Cited by 234 · see citing works
Westphal, J.-F. (2000) · British Journal of Clinical Pharmacology · doi:10.1046/j.1365-2125.2000.00261.x · Cited by 220 · see citing works
Clinical trials of p-glycoprotein reversal in solid tumours
Ferry, D., Traunecker, H., & Kerr, D. J. (1996) · European Journal of Cancer · doi:10.1016/0959-8049(96)00091-3 · Cited by 214 · see citing works
Resistance modification by PSC-833, a novel non-immunosuppressive cyclosporin A
Twentyman, P. R., & Bleehen, N. M. (1991) · European Journal of Cancer and Clinical Oncology · doi:10.1016/0277-5379(91)90435-g · Cited by 211 · see citing works
Phase I trial of doxorubicin with cyclosporine as a modulator of multidrug resistance.
Bartlett, N. L., Lum, B. L., Fisher, G. A., et al. (1994) · Journal of Clinical Oncology · doi:10.1200/jco.1994.12.4.835 · Cited by 189 · see citing works
Kuppens, I. E. L. M., Witteveen, E. O., Jewell, R. C., et al. (2007) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-06-2414 · Cited by 177 · see citing works
Kelly, R. J., Draper, D., Chen, C. C., et al. (2010) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-10-1725 · Cited by 173 · see citing works
Boote, D. J., Dennis, I. F., Twentyman, P. R., Osborne, R. J., LABURTE, C., Hensel, S., Smyth, J. F., Brampton, M., & Bleehen, N. M. (1996) · Journal of Clinical Oncology · doi:10.1200/jco.1996.14.2.610 · Cited by 172 · see citing works
Advani, R. H., Saba, H. I., Tallman, M. S., Rowe, J. M., Wiernik, P. H., Ramek, J., Dugan, K., Lum, B. L., Villena, J., Davis, R. E., et al. (1999) · Blood · doi:10.1182/blood.v93.3.787.403k30_787_795 · Cited by 158 · see citing works
Lhommé, C., Joly, F., Walker, J. L., Lissoni, A. A., Nicoletto, M. O., Manikhas, G. M., Baekelandt, M. M. O., Gordon, A. N., Fracasso, P. M., Mietlowski, W. L., et al. (2008) · Journal of Clinical Oncology · doi:10.1200/jco.2007.14.9807 · Cited by 158 · see citing works
Malingré, M. M., Beijnen, J. H., Rosing, H., et al. (2001) · British Journal of Cancer · doi:10.1054/bjoc.2000.1543 · Cited by 153 · see citing works
Sandler, A. B., Gordon, M. S., de Alwis, D. P., Pouliquen, I. J., Green, L., Marder, P., Chaudhary, A. K., Fife, K., Battiato, L. A., Sweeney, C. J., et al. (2004) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-03-0644 · Cited by 151 · see citing works
Friedenberg, W. R., Rué, M., Blood, E., et al. (2006) · Cancer · doi:10.1002/cncr.21666 · Cited by 146 · see citing works
Modulation of P‐glycoprotein but not MRP1‐ or BCRP‐mediated drug resistance by LY335979
Shepard, R. L., Cao, J., Starling, J. J., & Dantzig, A. H. (2002) · International Journal of Cancer · doi:10.1002/ijc.10792 · Cited by 138 · see citing works
Evaluation of antipsychotic drugs as inhibitors of multidrug resistance transporter P-glycoprotein
Wang, J.-S., Zhu, H., Markowitz, J. S., Donovan, J. L., & DeVane, C. L. (2006) · Psychopharmacology · doi:10.1007/s00213-006-0437-9 · Cited by 125 · see citing works
Stewart, A. J., Steiner, J., MELLOWS, G., Laguda, B., Norris, D., & Bevan, P. (2000) · PubMed · Cited by 122 · see citing works
Bauer, M., Zeitlinger, M. A., Karch, R., Matzneller, P., Stanek, J., Jäger, W. R., Böhmdorfer, M., Wadsak, W., Mitterhauser, M., Bankstahl, J. P., et al. (2011) · Clinical Pharmacology & Therapeutics · doi:10.1038/clpt.2011.217 · Cited by 119 · see citing works
A Phase I Study of the P-Glycoprotein Antagonist Tariquidar in Combination with Vinorelbine
Abraham, J., Edgerly, M., Wilson, R. H., et al. (2009) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-08-0938 · Cited by 116 · see citing works
Planting, A. S. T., Sonneveld, P., van der Gaast, A., et al. (2004) · Cancer Chemotherapy and Pharmacology · doi:10.1007/s00280-004-0854-6 · Cited by 106 · see citing works
Edoxaban drug–drug interactions with ketoconazole, erythromycin, and cyclosporine
Parasrampuria, D. A., Mendell, J., Shi, M., Matsushima, N., Zahir, H., & Truitt, K. E. (2016) · British Journal of Clinical Pharmacology · doi:10.1111/bcp.13092 · Cited by 104 · see citing works
Sparreboom, A., Planting, A. S. T., Jewell, R. C., van der Burg, M. E., van der Gaast, A., de Bruijn, P., Loos, W. J., Nooter, K., Chandler, L. H., Paul, E. M., et al. (1999) · Anti-Cancer Drugs · doi:10.1097/00001813-199909000-00005 · Cited by 94 · see citing works
Oliva, C. R., Zhang, W., Langford, C., Suto, M. J., & Griguer, C. E. (2017) · Oncotarget · doi:10.18632/oncotarget.17247 · Cited by 90 · see citing works
Dash, R. P., Babu, R. J., & Srinivas, N. R. (2017) · European Journal of Drug Metabolism and Pharmacokinetics · doi:10.1007/s13318-017-0411-4 · Cited by 85 · see citing works
Bauer, F., Kuntner, C., Bankstahl, J. P., Wanek, T., Bankstahl, M., Stanek, J., Mairinger, S., Dörner, B., Löscher, W., Müller, M., et al. (2010) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2010.06.057 · Cited by 80 · see citing works
Phase I/II trial of dexverapamil plus vinblastine for patients with advanced renal cell carcinoma.
Motzer, R. J., Lyn, P., Fischer, P., et al. (1995) · Journal of Clinical Oncology · doi:10.1200/jco.1995.13.8.1958 · Cited by 78 · see citing works
Fox, E., Widemann, B. C., Pastakia, D. J., Chen, C. C., Yang, S. X., Cole, D. E., & Balis, F. M. (2015) · Cancer Chemotherapy and Pharmacology · doi:10.1007/s00280-015-2845-1 · Cited by 71 · see citing works
Milroy, R. (1993) · British Journal of Cancer · doi:10.1038/bjc.1993.433 · Cited by 68 · see citing works
A pilot study of quinidine and epirubicin in the treatment of advanced breast cancer
Jones, R., Kerr, D. J., Harnett, A. N., et al. (1990) · British Journal of Cancer · doi:10.1038/bjc.1990.244 · Cited by 64 · see citing works
Repositioning antipsychotic chlorpromazine for treating colorectal cancer by inhibiting sirtuin 1
Lee, W., Lee, W.-T., Cheng, C., Chen, K., Chou, C., Chung, C., Sun, M.-S., Cheng, H., Ho, M.-N., & Lin, C. (2015) · Oncotarget · doi:10.18632/oncotarget.4768 · Cited by 58 · see citing works
Yang, C.-E., Lee, W., Cheng, H., Chung, C., Mi, F.-L., & Lin, C. (2019) · Chemico-Biological Interactions · doi:10.1016/j.cbi.2019.01.033 · Cited by 57 · see citing works
Kos, V. M., Kelnerić, Ž., Mikac, L., & Haber, V. E. (2010) · European Journal of Pharmaceutical Sciences · doi:10.1016/j.ejps.2010.05.016 · Cited by 55 · see citing works
Giaccone, G., & Pinedo, H. M. (1996) · The Oncologist · doi:10.1634/theoncologist.1-1-82 · Cited by 54 · see citing works
Lancet, J. E., Baer, M. R., Durán, G. E., et al. (2008) · Leukemia Research · doi:10.1016/j.leukres.2008.09.015 · Cited by 52 · see citing works
Bauer, M., Karch, R., Zeitlinger, M. A., et al. (2013) · Journal of Nuclear Medicine · doi:10.2967/jnumed.112.118232 · Cited by 50 · see citing works
Pachot, J. I., Botham, R. P., Haegele, K. D., & Hwang, K. (2003) · PubMed · Cited by 49 · see citing works
Warner, E., Hedley, D. W., Andrulis, I. L., Myers, R. E., Trudeau, M. G., Warr, D. G., Pritchard, K. I., Blackstein, M. E., Goss, P. E., Franssen, E., et al. (1998) · PubMed · Cited by 48 · see citing works
Quinolone antibiotics: a potential adjunct to intravesical chemotherapy for bladder cancer
Kamat, A. M., DeHaven, J. I., & Lamm, D. L. (1999) · Urology · doi:10.1016/s0090-4295(99)00064-3 · Cited by 48 · see citing works
Libby, E. N., & Hromas, R. (2010) · Blood · doi:10.1182/blood-2010-09-304311 · Cited by 48 · see citing works
PDE5 inhibitors enhance the lethality of standard of care chemotherapy in pediatric CNS tumor cells
Roberts, J. L., Booth, L. A., Conley, A., et al. (2014) · Cancer Biology & Therapy · doi:10.4161/cbt.28553 · Cited by 47 · see citing works
Potential synergistic effect of phosphodiesterase inhibitors with chemotherapy in lung cancer
Domvri, K., Zarogoulidis, P., Ziogas, N. K., Zarogoulidis, P., Petanidis, S., Porpodis, Κ., Kioseoglou, E., & Hohenforst‐Schmidt, W. (2017) · Journal of Cancer · doi:10.7150/jca.21783 · Cited by 47 · see citing works
Advani, R. H., Visani, G., Milligan, D., et al. (1999) · Advances in experimental medicine and biology · doi:10.1007/978-1-4615-4811-9_6 · Cited by 46 · see citing works
El-Naa, M. M., Othman, M. S., & Younes, S. F. (2016) · Drug Design Development and Therapy · doi:10.2147/dddt.s107490 · Cited by 44 · see citing works
Synthesis and evaluation of [11C]XR9576 to assess the function of drug efflux transporters using PET
Kawamura, K., Konno, F., Yui, J., et al. (2010) · Annals of Nuclear Medicine · doi:10.1007/s12149-010-0373-y · Cited by 41 · see citing works
Chow, L. Q. M., Barlési, F., Bertino, E. M., et al. (2019) · Annals of Oncology · doi:10.1093/annonc/mdz260 · Cited by 41 · see citing works
Gao, Y., Sun, T.-Y., Bai, W.-F., et al. (2019) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2019.111692 · Cited by 38 · see citing works
High dose oral tamoxifen and subcutaneous interferon alpha-2a for recurrent glioma
Chang, S. M., Barker, F. G., Huhn, S. L., et al. (1998) · Journal of Neuro-Oncology · doi:10.1023/a:1005826323652 · Cited by 37 · see citing works
Visani, G., Milligan, D. W., Leoni, F., et al. (2001) · Leukemia · doi:10.1038/sj.leu.2402117 · Cited by 34 · see citing works
Agarwal, S. K., Tong, B., Bueno, O. F., Menon, R. M., & Salem, A. H. (2018) · Advances in Therapy · doi:10.1007/s12325-018-0793-y · Cited by 28 · see citing works
Stupp, R., Bauer, J., Pagani, O., et al. (1998) · Annals of Oncology · doi:10.1023/a:1008495919071 · Cited by 24 · see citing works
Kurita, J.-I., Hirao, Y., Nakano, H., Fukunishi, Y., & Nishimura, Y. (2018) · Scientific Reports · doi:10.1038/s41598-018-31852-1 · Cited by 24 · see citing works
Giaccone, G., & Pinedo, H. M. (1996) · PubMed · Cited by 24 · see citing works
The Rationale for Repurposing Sildenafil for Lung Cancer Treatment
Keats, T., Rosengren, R. J., & Ashton, J. C. (2017) · Anti-Cancer Agents in Medicinal Chemistry · doi:10.2174/1871520617666171103100959 · Cited by 22 · see citing works
Clonal Hematopoiesis after Induction Chemotherapy for Acute Myeloid Leukemia
Steensma, D. P., & Ebert, B. L. (2018) · New England Journal of Medicine · doi:10.1056/nejme1802610 · Cited by 19 · see citing works
Punt, C. J. A., Voest, E. E., Tueni, E., et al. (1997) · British Journal of Cancer · doi:10.1038/bjc.1997.563 · Cited by 18 · see citing works
del Palacio, J. P., Díaz, C., Vergara, N., Algieri, F., Rodríguez‐Nogales, A., de Pedro, N., Rodríguez‐Cabezas, M. E., Genilloud, O., Gálvez, J., & Vicente, F. (2017) · Frontiers in Pharmacology · doi:10.3389/fphar.2017.00202 · Cited by 4 · see citing works
Heudobler, D., Schulz, C., Fischer, J., et al. (2019) · Annals of Oncology · doi:10.1093/annonc/mdz260.092 · Cited by 3 · see citing works
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- [33]Sandler A Gordon M De Alwis DP Pouliquen I Green L Marder P A Phase I trial of a potent P-glycoprotein inhibitor, zosuquidar trihydrochloride (LY335979), administered intravenously in combination with doxorubicin in patients with advanced malignancy. Clin Cancer Res an Off J Am Assoc Cancer Res (2004) 10(10): 3265–72. 10.1158/1078-0432.CCR-03-0644 15161679 · DOI
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Teleanu, R. I., Preda, M. D., Niculescu, A.-G., Vladâcenco, O., Radu, C. I., Grumezescu, A. M., & Teleanu, D. M. (2022) · Pharmaceutics · doi:10.3390/pharmaceutics14050987 · Cited by 200 · see citing works
The drug efflux pump MDR1 promotes intrinsic and acquired resistance to PROTACs in cancer cells
Kurimchak, A. M., Herrera-Montávez, C., Montserrat-Sangrà, S., Araiza-Olivera, D., Hu, J., Neumann-Domer, R., Kuruvilla, M., Bellacosa, A., Testa, J. R., Jin, J., et al. (2022) · Science Signaling · doi:10.1126/scisignal.abn2707 · Cited by 136 · see citing works
- Authors
- Lai, J.-I., Tseng, Y.-J., Chen, M.-H., Huang, C.-Y. F., & Chang, P. M.-H.
- Affiliations
- Taipei Veterans General Hospital (TW)
- National Yang Ming University (TW)
- Corresponding author
- Chang, Peter Mu-Hsin
- Venue
- Frontiers in Oncology
- Publisher
- Frontiers Media SA
- Published
- 2020-11-16
- Volume
- 10
- Pages
- 561936-561936
- ISSN
- 2234-943X (ISSN-L)
- PMC
- PMC7704056
- OpenAlex
- W3099097868
- Cited by
- 144
- References
- 73
- Citations by year
- 2026: 18 · 2025: 29 · 2024: 35 · 2023: 21 · 2022: 27 · 2021: 14
- FWCI
- 1.66
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Frontiers in Oncology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Topics
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Medicine › Antibiotic Resistance in Bacteria
- Keywords
- P-glycoprotein, drug repurposing, FDA-approved drugs, drug resistance, cancer therapeutics, small molecules, combination therapy, DrugBank
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