Screening of Photosensitizers-ATP Binding Cassette (ABC) Transporter Interactions

Overview

Journal Cancer Drug Resist

Date 2024 Oct 15

PMID 39403604

Authors

Shruti Vig

Payal Srivastava

Idrisa Rahman

Renee Jaranson

Anika Dasgupta

Robert Perttila

Petteri Uusimaa

Huang-Chiao Huang

Affiliations

Soon will be listed here.

Abstract

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 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. 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. 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.

References

Merlin J, Gautier H, Barberi-Heyob M, Teiten 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 Oncol. 2003; 22(4):733-9. View

Mansi M, Howley R, Chandratre S, Chen B . Inhibition of ABCG2 transporter by lapatinib enhances 5-aminolevulinic acid-mediated protoporphyrin IX fluorescence and photodynamic therapy response in human glioma cell lines. Biochem Pharmacol. 2022; 200:115031. PMC: 10258830. DOI: 10.1016/j.bcp.2022.115031. View

Celli J, Spring B, Rizvi I, Evans C, Samkoe K, Verma S . Imaging and photodynamic therapy: mechanisms, monitoring, and optimization. Chem Rev. 2010; 110(5):2795-838. PMC: 2896821. DOI: 10.1021/cr900300p. View

Allison R, Moghissi K . Photodynamic Therapy (PDT): PDT Mechanisms. Clin Endosc. 2013; 46(1):24-9. PMC: 3572346. DOI: 10.5946/ce.2013.46.1.24. View

Ethirajan M, Chen Y, Joshi P, Pandey R . The role of porphyrin chemistry in tumor imaging and photodynamic therapy. Chem Soc Rev. 2010; 40(1):340-62. DOI: 10.1039/b915149b. View

Choi Y, Yu A . ABC transporters in multidrug resistance and pharmacokinetics, and strategies for drug development. Curr Pharm Des. 2013; 20(5):793-807. PMC: 6341993. DOI: 10.2174/138161282005140214165212. View

Liang B, Lusvarghi S, Ambudkar S, Huang H . Mechanistic Insights into Photodynamic Regulation of Adenosine 5'-Triphosphate-Binding Cassette Drug Transporters. ACS Pharmacol Transl Sci. 2022; 4(5):1578-1587. PMC: 9476936. DOI: 10.1021/acsptsci.1c00138. View

Shukla S, Chen Z, Ambudkar S . Tyrosine kinase inhibitors as modulators of ABC transporter-mediated drug resistance. Drug Resist Updat. 2012; 15(1-2):70-80. PMC: 3348341. DOI: 10.1016/j.drup.2012.01.005. View

Liu W, Baer M, Bowman M, Pera P, Zheng X, Morgan J . The tyrosine kinase inhibitor imatinib mesylate enhances the efficacy of photodynamic therapy by inhibiting ABCG2. Clin Cancer Res. 2007; 13(8):2463-70. DOI: 10.1158/1078-0432.CCR-06-1599. View

10.

Jonker J, Buitelaar M, Wagenaar E, van der Valk M, Scheffer G, Scheper R . The breast cancer resistance protein protects against a major chlorophyll-derived dietary phototoxin and protoporphyria. Proc Natl Acad Sci U S A. 2002; 99(24):15649-54. PMC: 137771. DOI: 10.1073/pnas.202607599. View

11.

Kim Y, Chen J . Molecular structure of human P-glycoprotein in the ATP-bound, outward-facing conformation. Science. 2018; 359(6378):915-919. DOI: 10.1126/science.aar7389. View

12.

Jackson S, Manolaridis I, Kowal J, Zechner M, Taylor N, Bause M . Structural basis of small-molecule inhibition of human multidrug transporter ABCG2. Nat Struct Mol Biol. 2018; 25(4):333-340. DOI: 10.1038/s41594-018-0049-1. View

13.

Wu C, Calcagno A, Ambudkar S . Reversal of ABC drug transporter-mediated multidrug resistance in cancer cells: evaluation of current strategies. Curr Mol Pharmacol. 2008; 1(2):93-105. PMC: 2600768. DOI: 10.2174/1874467210801020093. View

14.

Robey R, Steadman K, Polgar O, Morisaki K, Blayney M, Mistry P . Pheophorbide a is a specific probe for ABCG2 function and inhibition. Cancer Res. 2004; 64(4):1242-6. DOI: 10.1158/0008-5472.can-03-3298. View

15.

Li W, Zhang W, Ohnishi K, Yamada I, Ohno R, Hashimoto K . 5-Aminolaevulinic acid-mediated photodynamic therapy in multidrug resistant leukemia cells. J Photochem Photobiol B. 2001; 60(2-3):79-86. DOI: 10.1016/s1011-1344(01)00124-5. View

16.

Yuan Y, Chen K, Chen X, Wang C, Qiu H, Cao Z . Fumitremorgin C Attenuates Osteoclast Formation and Function Suppressing RANKL-Induced Signaling Pathways. Front Pharmacol. 2020; 11:238. PMC: 7076231. DOI: 10.3389/fphar.2020.00238. View

17.

Dougherty T, Gomer C, Henderson B, Jori G, Kessel D, Korbelik M . Photodynamic therapy. J Natl Cancer Inst. 1998; 90(12):889-905. PMC: 4592754. DOI: 10.1093/jnci/90.12.889. View

18.

Tsai T, Hong R, Tsai J, Lou P, Ling I, Chen C . Effect of 5-aminolevulinic acid-mediated photodynamic therapy on MCF-7 and MCF-7/ADR cells. Lasers Surg Med. 2004; 34(1):62-72. DOI: 10.1002/lsm.10246. View

19.

Fathy G, Asaad M, Rasheed H . Daylight photodynamic therapy with methylene blue in plane warts: a randomized double-blind placebo-controlled study. Photodermatol Photoimmunol Photomed. 2017; 33(4):185-192. DOI: 10.1111/phpp.12291. View

20.

Dolmans D, Fukumura D, Jain R . Photodynamic therapy for cancer. Nat Rev Cancer. 2003; 3(5):380-7. DOI: 10.1038/nrc1071. View