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The carotenoid fucoxanthin can sensitize multidrug resistant cancer cells to doxorubicin via induction of apoptosis, inhibition of multidrug resistance proteins and metabolic enzymes.
Phytomedicine. 2020 Oct; 77:153280.P

Abstract

BACKGROUND

Multidrug resistance (MDR) causes failure of doxorubicin therapy of cancer cells, which develops after or during doxorubicin treatment resulting in cross-resistance to structurally and functionally-unrelated other anticancer drugs. MDR is multifactorial phenomenon associated with overexpression of ATP-binding cassette (ABC) transporters, metabolic enzymes, impairment of apoptosis, and alteration of cell cycle checkpoints. The cancer-prevention of the dietary carotenoid; fucoxanthin (FUC) has been extensively explored. Nevertheless, the underlying mechanism of its action is not full elucidated.

HYPOTHESIS/PURPOSE

Investigation of the underlying mechanism of MDR reversal by the dietary carotenoid fucoxanthin (FUC) and its ability to enhance the doxorubicin (DOX) cytotoxicity in resistant breast (MCF-7/ADR), hepatic (HepG-2/ADR), and ovarian (SKOV-3/ADR) cell lines.

METHODS

The synergistic interaction of FUC and DOX was evaluated using several techniques, viz.; MTT assay, ABC transporter function assays using FACS and fluorimetry, enzyme activity via spectroscopy and luminescence assays, and apoptosis assay using FACS, and gene expression using RTPCR.

RESULTS

FUC (20 µM) synergistically enhanced the cytotoxicity of DOX and significantly reduced the dose of DOX (FR) in DOX resistant cells (MCF-7/ADR), hepatic (HepG-2/ADR), and ovarian (SKOV-3/ADR) to 8.42-(CI= 0.25), 6.28-(CI= 0.32), and 4.56-fold (CI=0.37) (P<0.001). FUC significantly increased the accumulation of DOX more than verapamil in resistant cells by 2.70, 2.67, and 3.95-fold of untreated cells (p<0.001), respectively. A FUC and DOX combination significantly increased the Rho123 accumulation higher than individual drugs by 2.36-, 2.38-, 1.89-fold verapamil effects in tested cells (p<0.001), respectively. The combination of the FUC and DOX decreased ABCC1, ABCG2, and ABCB1 expression. The FUC and DOX combination increased the levels and activity of caspases (CASP3, CASP8) and p53, while decreased the levels and activity of CYP3A4, GST, and PXR in resistant cancer cells. The combination induced early/late apoptosis to 91.9/5.4% compared with 0.0/0.7% of untreated control.

CONCLUSION

Our data suggests a new dietary and therapeutic approach of combining the FUC with DOX to overcome multidrug resistance in cancer cells. However, animal experiments should be conducted to confirm the findings before applying the results into clinical trials.

Authors+Show Affiliations

Department of Biochemistry, Faculty of Medicine, Umm Al-Qura University, Makkah, K.S.A.Department of Biochemistry, Faculty of Medicine, Umm Al-Qura University, Makkah, K.S.A.Department of Biochemistry, Faculty of Medicine, Umm Al-Qura University, Makkah, K.S.A.Department of Pharmaceutical Biology, Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, Im Neuenheimer Feld 364, 69120 Heidelberg, Germany.Department of Biochemistry, Faculty of Medicine, Umm Al-Qura University, Makkah, K.S.A; Department of Biochemistry, Faculty of Pharmacy, Al-Azhar University, 71524 Assiut, Egypt. Electronic address: mzreadi@uqu.edu.sa.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32712543

Citation

Eid, Safaa Yehia, et al. "The Carotenoid Fucoxanthin Can Sensitize Multidrug Resistant Cancer Cells to Doxorubicin Via Induction of Apoptosis, Inhibition of Multidrug Resistance Proteins and Metabolic Enzymes." Phytomedicine : International Journal of Phytotherapy and Phytopharmacology, vol. 77, 2020, p. 153280.
Eid SY, Althubiti MA, Abdallah ME, et al. The carotenoid fucoxanthin can sensitize multidrug resistant cancer cells to doxorubicin via induction of apoptosis, inhibition of multidrug resistance proteins and metabolic enzymes. Phytomedicine. 2020;77:153280.
Eid, S. Y., Althubiti, M. A., Abdallah, M. E., Wink, M., & El-Readi, M. Z. (2020). The carotenoid fucoxanthin can sensitize multidrug resistant cancer cells to doxorubicin via induction of apoptosis, inhibition of multidrug resistance proteins and metabolic enzymes. Phytomedicine : International Journal of Phytotherapy and Phytopharmacology, 77, 153280. https://doi.org/10.1016/j.phymed.2020.153280
Eid SY, et al. The Carotenoid Fucoxanthin Can Sensitize Multidrug Resistant Cancer Cells to Doxorubicin Via Induction of Apoptosis, Inhibition of Multidrug Resistance Proteins and Metabolic Enzymes. Phytomedicine. 2020;77:153280. PubMed PMID: 32712543.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The carotenoid fucoxanthin can sensitize multidrug resistant cancer cells to doxorubicin via induction of apoptosis, inhibition of multidrug resistance proteins and metabolic enzymes. AU - Eid,Safaa Yehia, AU - Althubiti,Mohammad Ahmad, AU - Abdallah,Mohamed E, AU - Wink,Michael, AU - El-Readi,Mahmoud Zaki, Y1 - 2020/07/08/ PY - 2020/04/10/received PY - 2020/06/12/revised PY - 2020/07/07/accepted PY - 2020/7/28/pubmed PY - 2020/12/18/medline PY - 2020/7/27/entrez KW - Carotenoids KW - Chemoprevention of cancer KW - DOX KW - Fucoxanthin KW - Multidrug resistance SP - 153280 EP - 153280 JF - Phytomedicine : international journal of phytotherapy and phytopharmacology JO - Phytomedicine VL - 77 N2 - BACKGROUND: Multidrug resistance (MDR) causes failure of doxorubicin therapy of cancer cells, which develops after or during doxorubicin treatment resulting in cross-resistance to structurally and functionally-unrelated other anticancer drugs. MDR is multifactorial phenomenon associated with overexpression of ATP-binding cassette (ABC) transporters, metabolic enzymes, impairment of apoptosis, and alteration of cell cycle checkpoints. The cancer-prevention of the dietary carotenoid; fucoxanthin (FUC) has been extensively explored. Nevertheless, the underlying mechanism of its action is not full elucidated. HYPOTHESIS/PURPOSE: Investigation of the underlying mechanism of MDR reversal by the dietary carotenoid fucoxanthin (FUC) and its ability to enhance the doxorubicin (DOX) cytotoxicity in resistant breast (MCF-7/ADR), hepatic (HepG-2/ADR), and ovarian (SKOV-3/ADR) cell lines. METHODS: The synergistic interaction of FUC and DOX was evaluated using several techniques, viz.; MTT assay, ABC transporter function assays using FACS and fluorimetry, enzyme activity via spectroscopy and luminescence assays, and apoptosis assay using FACS, and gene expression using RTPCR. RESULTS: FUC (20 µM) synergistically enhanced the cytotoxicity of DOX and significantly reduced the dose of DOX (FR) in DOX resistant cells (MCF-7/ADR), hepatic (HepG-2/ADR), and ovarian (SKOV-3/ADR) to 8.42-(CI= 0.25), 6.28-(CI= 0.32), and 4.56-fold (CI=0.37) (P<0.001). FUC significantly increased the accumulation of DOX more than verapamil in resistant cells by 2.70, 2.67, and 3.95-fold of untreated cells (p<0.001), respectively. A FUC and DOX combination significantly increased the Rho123 accumulation higher than individual drugs by 2.36-, 2.38-, 1.89-fold verapamil effects in tested cells (p<0.001), respectively. The combination of the FUC and DOX decreased ABCC1, ABCG2, and ABCB1 expression. The FUC and DOX combination increased the levels and activity of caspases (CASP3, CASP8) and p53, while decreased the levels and activity of CYP3A4, GST, and PXR in resistant cancer cells. The combination induced early/late apoptosis to 91.9/5.4% compared with 0.0/0.7% of untreated control. CONCLUSION: Our data suggests a new dietary and therapeutic approach of combining the FUC with DOX to overcome multidrug resistance in cancer cells. However, animal experiments should be conducted to confirm the findings before applying the results into clinical trials. SN - 1618-095X UR - https://www.unboundmedicine.com/medline/citation/32712543/The_carotenoid_fucoxanthin_can_sensitize_multidrug_resistant_cancer_cells_to_doxorubicin_via_induction_of_apoptosis_inhibition_of_multidrug_resistance_proteins_and_metabolic_enzymes_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0944-7113(20)30111-2 DB - PRIME DP - Unbound Medicine ER -