Screening of photosensitizers-ATP binding cassette (ABC) transporter interactions in vitro

Abstract

Aim: ATP-binding cassette (ABC) transporters are proteins responsible for the efflux of drug molecules from cancer cells, reducing the efficacy of anti-cancer treatments. This study assesses the susceptibility of a panel of clinically used photosensitizers to be transported by ABC transporters in vitro.

Methods: The involvement of P-glycoprotein (P-gp/ABCB1), breast cancer resistance protein (BCRP/ABCG2), and multidrug resistance-associated protein 1 (MRP1/ABCC1) in the transport of 7 clinically utilized photosensitizers [benzoporphyrin derivative (BPD), temoporfin, redaporfin, talaporfin sodium, rose bengal, methylene blue, and indocyanine green] were investigated using human breast cancer cell lines following well-established protocols. Briefly, parental MCF-7 cells and sublines that overexpress P-gp (MCF-7 TX400), ABCG2 (MCF-7 MX100), or MRP1 (MCF-7/VP) were treated with photosensitizers with and without ABC transporter inhibitors. Intracellular levels of photosensitizers were measured using extraction method and flow cytometry to determine whether the ABC transporters are associated with efflux or uptake of photosensitizers.

Results: The ABCG2 inhibitor (fumitremorgin C) and P-gp inhibitor (valspodar) effectively blocked the transport mediated by ABCG2 and P-gp of rose bengal and BPD. Redaporfin showed increased accumulation in the presence of valspodar with flow cytometry. Interestingly, MCF-7/VP cells were found to have reduced intracellular accumulation of rose bengal, which was restored with MRP1 inhibitor (MK571). The cell viability assay showed photodynamic therapy (PDT) resistance with Redaporfin in P-gp-overexpressing cells, BPD in ABCG2- and P-gp-overexpressing cells, and with Rose bengal in ABCG2-, P-gp- and MRP1-overexpressing cells, respectively. However, no change in intracellular retention was observed for other photosensitizers.

Conclusion: In summary, our study provided new knowledge that temoporfin, talaporfin sodium, methylene blue, and indocyanine green are not substrates of ABCG2, P-gp, or MRP1. Redaporfin is a substrate for P-gp. BPD is a known substrate of ABCG2 and P-gp. Rose bengal is a substrate of ABCG2, P-gp, and MRP1. The results presented here indicate ABC transporter substrate status as a possible cause for cellular resistance to photodynamic therapy with rose bengal, redaporfin, and BPD.

Keywords

Multidrug resistance / ATP-binding cassette (ABC) transporters / photosensitizers / photodynamic therapy

References

[1] Obaid G,Broekgaarden M.Engineering photodynamics for treatment, priming and imaging.Nat Rev Bioeng2024;2:752-69

[2] Dolmans DEJGJ,Jain RK.Photodynamic therapy for cancer.Nat Rev Cancer2003;3:380-7

[3] Celli JP,Rizvi I.Imaging and photodynamic therapy: mechanisms, monitoring, and optimization.Chem Rev2010;110:2795-838 PMCID:PMC2896821

[4] Allison RR.Photodynamic therapy (PDT): PDT mechanisms.Clin Endosc2013;46:24-9 PMCID:PMC3572346

[5] Ethirajan M,Joshi P.The role of porphyrin chemistry in tumor imaging and photodynamic therapy.Chem Soc Rev2011;40:340-62

[6] Dougherty TJ,Henderson BW.Photodynamic therapy.J Natl Cancer Inst1998;90:889-905 PMCID:PMC4592754

[7] Abrahamse H.New photosensitizers for photodynamic therapy.Biochem J2016;473:347-64 PMCID:PMC4811612

[8] Scott LJ.Verteporfin.Drugs Aging2000;16:139-46

[9] ClinicalTrials.gov. Treatment of primary breast cancer using PDT. Available from: https://clinicaltrials.gov/study/NCT02872064. [Last accessed on 13 Sep 2024]

[10] ClinicalTrials.gov. An open label, phase II trial of continuous low-irradiance photodynamic therapy (CLIPT) using Verteporfin (Visudyne®) for the treatment of cutaneous metastases of breast cancer. Available from: https://clinicaltrials.gov/study/NCT02939274. [Last accessed on 13 Sep 2024]

[11] ClinicalTrials.gov. Ultrasound-guided verteporfin photodynamic therapy for the treatment of unresectable solid pancreatic tumors or advanced pancreatic cancer, VERTPAC-02 study. Available from: https://clinicaltrials.gov/study/NCT03033225. [Last accessed on 13 Sep 2024]

[12] ClinicalTrials.gov. Photodynamic therapy in treating patients with stage III or stage IV melanoma. Available from: https://clinicaltrials.gov/study/NCT00007969. [Last accessed on 13 Sep 2024]

[13] ClinicalTrials.gov. Interstitial photodynamic therapy following palliative radiotherapy in treating patients with inoperable malignant central airway obstruction. Available from: https://clinicaltrials.gov/study/NCT06306638. [Last accessed on 13 Sep 2024]

[14] ClinicalTrials.gov. Verteporfin for the treatment of recurrent high-grade EGFR-mutated glioblastoma. Available from: https://clinicaltrials.gov/study/NCT04590664. [Last accessed on 13 Sep 2024]

[15] European Medicines Agency. Foscan. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/foscan. [Last accessed on 13 Sep 2024]

[16] ClinicalTrials.gov. Single-arm study of photodynamic laser therapy using foscan for non-curatively-resectable bile duct carcinoma. Available from: https://clinicaltrials.gov/study/NCT01016002. [Last accessed on 13 Sep 2024]

[17] ClinicalTrials.gov. Safety and tumoricidal effect of low dose foscan PDT in Patients with inoperable bile duct cancers (PDT). Available from: https://clinicaltrials.gov/study/NCT03003065. [Last accessed on 13 Sep 2024]

[18] ClinicalTrials.gov. Photodynamic therapy during surgery in treating patients with non-small cell lung cancer that can be removed by surgery. Available from: https://clinicaltrials.gov/study/NCT01854684. [Last accessed on 13 Sep 2024]

[19] Wang S,Xu L,Keltner L.Talaporfin sodium.Expert Opin Pharmacother2010;11:133-40

[20] ClinicalTrials.gov. A phase 3 study of talaporfin sodium and interstitial light emitting diodes treating hepatocellular carcinoma (HCC). Available from: https://clinicaltrials.gov/study/NCT00355355. [Last accessed on 13 Sep 2024]

[21] ClinicalTrials.gov. Tumor ablation with talaporfin sodium and interstitial light emitting diodes treating hepatocellular carcinoma (HCC). Available from: https://clinicaltrials.gov/study/NCT00122876. [Last accessed on 13 Sep 2024]

[22] ClinicalTrials.gov. Photodynamic therapy with talaporfin sodium (LS11) in treating patients with refractory colorectal liver metastases. Available from: https://clinicaltrials.gov/study/NCT00068068. [Last accessed on 13 Sep 2024]

[23] European Medicines Agency. EU/3/22/2602 - orphan designation for the treatment of biliary tract cancer. 2022. Available from: https://www.ema.europa.eu/en/medicines/human/orphan-designations/eu-3-15-1470. [Last accessed on 13 Sep 2024]

[24] Santos LL,Monteiro E,Sarmento C.Treatment of head and neck cancer with photodynamic therapy with redaporfin: a clinical case report.Case Rep Oncol2018;11:769-76 PMCID:PMC6323365

[25] Dos Santos AF,Wailemann RA.Methylene blue photodynamic therapy induces selective and massive cell death in human breast cancer cells.BMC Cancer2017;17:194 PMCID:PMC5353937

[26] Tardivo JP,de Oliveira CS.Methylene blue in photodynamic therapy: From basic mechanisms to clinical applications.Photodiagnosis Photodyn Ther2005;2:175-91

[27] Fathy G,Rasheed HM.Daylight photodynamic therapy with methylene blue in plane warts: a randomized double-blind placebo-controlled study.Photodermatol Photoimmunol Photomed2017;33:185-92

[28] ClinicalTrials.gov. ICG-PDT, periimplantitis, diabetes mellitus. Available from: https://clinicaltrials.gov/study/NCT04833569. [Last accessed on 13 Sep 2024]

[29] ClinicalTrials.gov. Single session of antimicrobial photodynamic therapy using indocyanine green. Available from: https://clinicaltrials.gov/study/NCT02043340. [Last accessed on 13 Sep 2024]

[30] Leonard GD,Bates SE.The role of ABC transporters in clinical practice.Oncologist2003;8:411-24

[31] Kim Y.Molecular structure of human P-glycoprotein in the ATP-bound, outward-facing conformation.Science2018;359:915-9

[32] Manolaridis I,Taylor NMI,Stahlberg H.Cryo-EM structures of a human ABCG2 mutant trapped in ATP-bound and substrate-bound states.Nature2018;563:426-30. PMCID:PMC6379061

[33] Schinkel AH.Mammalian drug efflux transporters of the ATP binding cassette (ABC) family: an overview.Adv Drug Deliv Rev2003;55:3-29

[34] Gottesman MM,Hall MD.Toward a better understanding of the complexity of cancer drug resistance.Annu Rev Pharmacol Toxicol2016;56:85-102

[35] Tamaki A,Szakacs G,Bates SE.The controversial role of ABC transporters in clinical oncology.Essays Biochem2011;50:209-32 PMCID:PMC6944313

[36] Baglo Y,Robey RW,Gottesman MM.Porphyrin-lipid assemblies and nanovesicles overcome ABC transporter-mediated photodynamic therapy resistance in cancer cells.Cancer Lett2019;457:110-8 PMCID:PMC6690745

[37] Li W,Ohnishi K,Ohno R.5-Aminolaevulinic acid-mediated photodynamic therapy in multidrug resistant leukemia cells.J Photochem Photobiol B2001;60:79-86

[38] Robey RW,Polgar O.Pheophorbide a is a specific probe for ABCG2 function and inhibition.Cancer Res2004;64:1242-6

[39] Jonker JW,Wagenaar E.The breast cancer resistance protein protects against a major chlorophyll-derived dietary phototoxin and protoporphyria.Proc Natl Acad Sci U S A2002;99:15649-54 PMCID:PMC137771

[40] Merlin JL,Barberi-Heyob M,Guillemin F.The multidrug resistance modulator SDZ-PSC 833 potentiates the photodynamic activity of chlorin e6 independently of P-glycoprotein in multidrug resistant human breast adenocarcinoma cells.Int J Oncol2003;22:733-9

[41] Robey RW,Polgar O.ABCG2-mediated transport of photosensitizers: potential impact on photodynamic therapy.Cancer Biol Ther2005;4:187-94

[42] Huang HC,Liu J.Photodynamic therapy synergizes with irinotecan to overcome compensatory mechanisms and improve treatment outcomes in pancreatic cancer.Cancer Res2016;76:1066-77 PMCID:PMC4775276

[43] Aniogo EC,Abrahamse H.The role of photodynamic therapy on multidrug resistant breast cancer.Cancer Cell Int2019;19:91 PMCID:PMC6458738

[44] Bartholomae S,Debatin KM.Co-expression of multiple ABC-transporters is strongly associated with treatment response in childhood acute myeloid leukemia.Pediatr Blood Cancer2016;63:242-7

[45] Ween MP,Oehler MK.The role of ABC transporters in ovarian cancer progression and chemoresistance.Crit Rev Oncol Hematol2015;96:220-56

[46] Hlavata I,Vaclavikova R.The role of ABC transporters in progression and clinical outcome of colorectal cancer.Mutagenesis2012;27:187-96

[47] Casas A,Hasan T.Mechanisms of resistance to photodynamic therapy.Curr Med Chem2011;18:2486-515 PMCID:PMC3780570

[48] Kukcinaviciute E,Dabkeviciene D,Jonusiene V.Effect of mTHPC-mediated photodynamic therapy on 5-fluorouracil resistant human colorectal cancer cells.Photochem Photobiol Sci2017;16:1063-70

[49] Kim JH,Roh YJ,Hasan T.Enhanced efficacy of photodynamic therapy by inhibiting ABCG2 in colon cancers.BMC Cancer2015;15:504 PMCID:PMC4494642

[50] Liu FS.Mechanisms of chemotherapeutic drug resistance in cancer therapy--a quick review.Taiwan J Obstet Gynecol2009;48:239-44

[51] Yuan Y,Chen X.Fumitremorgin C attenuates osteoclast formation and function via suppressing RANKL-induced signaling pathways.Front Pharmacol2020;11:238 PMCID:PMC7076231

[52] Jackson SM,Kowal J.Structural basis of small-molecule inhibition of human multidrug transporter ABCG2.Nat Struct Mol Biol2018;25:333-40

[53] Nagaya T,Choyke PL.Fluorescence-guided surgery.Front Oncol2017;7:314 PMCID:PMC5743791

[54] Liu W,Bowman MJ.The tyrosine kinase inhibitor imatinib mesylate enhances the efficacy of photodynamic therapy by inhibiting ABCG2.Clin Cancer Res2007;13:2463-70

[55] Teiten MH,Merlin JL.Effect of meta-tetra(hydroxyphenyl)chlorin (mTHPC)-mediated photodynamic therapy on sensitive and multidrug-resistant human breast cancer cells.J Photochem Photobiol B2001;62:146-52

[56] Tsai T,Tsai JC,Ling IF.Effect of 5-aminolevulinic acid-mediated photodynamic therapy on MCF-7 and MCF-7/ADR cells.Lasers Surg Med2004;34:62-72

[57] Sajid A,Ambudkar SV.Advances in the structure, mechanism and targeting of chemoresistance-linked ABC transporters.Nat Rev Cancer2023;23:762-79

[58] Montanari F.Prediction of drug-ABC-transporter interaction - recent advances and future challenges.Adv Drug Deliv Rev2015;86:17-26 PMCID:PMC6422311

[59] Liang BJ,Ambudkar SV.Mechanistic insights into photodynamic regulation of adenosine 5’-triphosphate-binding cassette drug transporters.ACS Pharmacol Transl Sci2021;4:1578-87 PMCID:PMC9476936

[60] Palasuberniam P,Kraus D,Myers KA.ABCG2 transporter inhibitor restores the sensitivity of triple negative breast cancer cells to aminolevulinic acid-mediated photodynamic therapy.Sci Rep2015;5:13298 PMCID:PMC4539603

[61] Mansi M,Chandratre S.Inhibition of ABCG2 transporter by lapatinib enhances 5-aminolevulinic acid-mediated protoporphyrin IX fluorescence and photodynamic therapy response in human glioma cell lines.Biochem Pharmacol2022;200:115031 PMCID:PMC10258830

[62] Lee HJ,Cho JY.A phase i study of oral paclitaxel with a novel p-glycoprotein inhibitor, HM30181A, in patients with advanced solid cancer.Cancer Res Treat2014;46:234-42 PMCID:PMC4132447

[63] Choi YH.ABC transporters in multidrug resistance and pharmacokinetics, and strategies for drug development.Curr Pharm Des2014;20:793-807 PMCID:PMC6341993

[64] Wu CP,Ambudkar SV.Reversal of ABC drug transporter-mediated multidrug resistance in cancer cells: evaluation of current strategies.Curr Mol Pharmacol2008;1:93-105 PMCID:PMC2600768

[65] Shukla S,Ambudkar SV.Tyrosine kinase inhibitors as modulators of ABC transporter-mediated drug resistance.Drug Resist Updat2012;15:70-80 PMCID:PMC3348341

[66] Wu CP,Huang YH.Sitravatinib Sensitizes ABCB1- and ABCG2-overexpressing multidrug-resistant cancer cells to chemotherapeutic drugs.Cancers2020;12:195 PMCID:PMC7017071

[67] Rahman I,Sajid A,Huang HC.Photodynamic priming modulates cellular ATP levels to overcome P-glycoprotein-mediated drug efflux in chemoresistant triple-negative breast cancer.Photochem Photobiol2024;Online ahead of print:

[68] ClinicalTrials.gov. Photodynamic therapy in treating patients with cancer of the bile duct, gallbladder, or pancreas. Available from: https://clinicaltrials.gov/study/NCT00003923. [Last accessed on 13 Sep 2024]

[69] Heinzelmann-Schwarz V,Hornung R,Haller U.Role of p53 and ATM in photodynamic therapy-induced apoptosis.Lasers Surg Med2003;33:182-9

[70] Luna MC,Wong S,Gomer CJ.Photodynamic therapy-mediated oxidative stress as a molecular switch for the temporal expression of genes ligated to the human heat shock promoter.CancerRes2000;60:1637-44

[71] Rodriguez L,Rivas MA,Sanz-Rodriguez F.Ras-transfected human mammary tumour cells are resistant to photodynamic therapy by mechanisms related to cell adhesion.Life Sci2023;314:121287