The Drug Transporter P-Glycoprotein and Its Impact on Ceramide Metabolism—An Unconventional Ally in Cancer Treatment
Abstract
:1. Sphingolipid Metabolism at a Glance
1.1. The De Novo Pathway of Ceramide Formation
1.2. Ceramide Metabolism—Intracellular Fate
1.3. Bioactive Sphingolipids
2. An Introduction to Chemotherapy Resistance
2.1. Factors Contributing to Chemotherapy Resistance
2.2. Drug Activation/Inactivation—Drug Metabolism
2.3. Repairing DNA Damage
2.4. Resistance to Apoptosis
2.5. Interplay between ABC Transporters and Sphingolipid Metabolism—Blunting of the “Ceramide Effect”
3. Chemotherapy Drugs and Sphingolipid Metabolism
3.1. Chemotherapy Selection Pressure Promotes Alterations in Sphingolipid Metabolism
3.2. Ceramide Glycosylation—A Factor in Anthracycline and Vinca Alkaloid Resistance
3.3. Ceramide Glycosylation in Sorafenib, Imatinib, and Platinum Resistance
4. Manipulating GCS Modifies Response to Chemotherapy
5. P-gp, GCS, and Ceramide Glycosylation—Cozy Cooperation
6. P-gp “The Chemotherapy Efflux Pump” versus P-gp “The Ceramide Neutralizer”—Versatility in Drug Resistance
7. P-gp Antagonists and GCS Inhibitors—Duplicitous Roles
8. Do We Target GCS or P-gp to Enhance the Ceramide Effect?
9. Summary and Conclusions
Funding
Acknowledgments
Conflicts of Interest
References
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Action | Agents | Model | Reference |
---|---|---|---|
A. Increase Adriamycin sensitivity | Tamoxifen; PPMP | MCF-7/AdrR cells (Adriamycin-resistant, human ovarian cancer cell line) | [104] |
B. Increase Taxol, vincristine sensitivity | PDMP | MCF-7/AdrR | [156] |
C. Increase C6-ceramide sensitivity | Tamoxifen; tariquidar; zosuquidar; cyclosporin A | HL-60/VCR (vincristine-resistant human acute myeloid leukemia cell line); KG-1a (human acute myeloid cell line); LoVo (human colon cancer cell line) | [158] |
D. Enhance C8-ceramide sensitivity | Elacridar; cyclosporin A | KG-1a; TF-1 (human acute myeloid leukemia cell lines) | [162] |
E. Increase C6-ceramide sensitivity | Tamoxifen | P-gp-overexpressing HeLa cells | [163] |
F. Increase daunorubicin and vincristine sensitivity; increase rhodamine retention | PDMP | KG-1a/200 (daunorubicin- and vincristine-resistant); K562/138 (vincristine-resistant chronic myeloid leukemia cell line); K562/MDR-1 (stably transfected to express MDR-1) | [167] |
G. Reverse daunorubicin resistance; enhance daunorubicin accumulation | PDMP; tetrandrine | K562/A02 (Adriamycin-resistant) | [168] |
H. Enhanced C6-, C8-ceramide cytotoxicity | Tamoxifen; cyclosporin A; VX-710 (Biricodar); P4 (analog of PPPP) | 2780AD (doxorubicin-resistant human ovarian cancer cell line); NCI/ADR-RES (doxorubicin-resistant, human ovarian cancer cell line) | [164] |
I. Increase sensitivity to Taxol and vincristine; decrease efflux | PDMP; PSC833 (Valspodar); MK571 | Neuro-2a; C1300 (murine neuroblastoma cell lines) | [170] |
J. Sensitize drug-resistant cells to chemotherapy (Vincas; Adriamycin; Taxotere) | Genz-123346; PDMP; verapamil | KBV-1 (human cervical carcinoma cell line); HCT-15 (human colorectal cancer cell line) | [171] |
K. Reverse Imatinib resistance | PDMP | K562/IMA (imatinib-resistant chronic myeloid leukemia cell line) | [17] |
L. Reverse Cisplatin resistance | PDMP | Orthoxenografts, testicular germ cell tumors | [174] |
M. Reverse Fludarabine resistance | PDMP | Fludarabine-resistant MEC-2 cells (human B cell leukemia cell line) | [175] |
N. Enhance sensitivity to Taxol and cisplatin | PDMP | Paclitaxel-resistant PX2 and KF28; cisplatin-resistant C13 and KFr13 (human ovarian cancer cell lines) | [176] |
O. Enhance selumetinib (AZD-6244) sensitivity | PDMP | PANC-1; AsPC-1; MIA PaCa-2 (human pancreatic cancer cell lines) | [177] |
P. Increase sensitivity to C6-ceramide nanoliposome (CNL) | PDMP | PANC-1 | [178] |
Q. Enhance vinorelbine sensitivity | PDMP | A549; CL1-5 (human lung adenocarcinoma cell lines) | [179] |
R. Sensitization to ABT-263 (Bcl-2 inhibitor) | PDMP | U937; K562; HL-60; RPMI-8226 (various human leukemia cell lines) | [180] |
S. Enhance AR-42 (HDAC inhibitor) sensitivity | PDMP | SW-620 (human colon cancer cell line) | [181] |
T. Potentiate A-674563 (Akt1 inhibitor) cytotoxicity | PDMP | A375 (human melanoma cell line) | [182] |
U. Sensitize to GNF-2 (Bcr-Abl inhibitor); imatinib; nilotinib | PDMP | K562; Ba/F3-p210T315I (Bcr-Abl mutant murine chronic myeloid leukemia cell line) | [183] |
V. Enhance vincristine and Adriamycin sensitivity; decrease drug efflux | Mifepristone | SGC7901/VCR (vincristine-resistant human gastric cancer cell line); rat hepatoma cells; K562-R7 (multidrug-resistant) | [184,185] |
W. Enhance sensitivity to Taxol and Adriamycin | Resveratrol | MCF-7; HepG2, HeLa (various human solid tumor cell lines) | [186] |
X. Enhance vincristine, daunorubicin, cisplatin sensitivity | Ethylenedioxy-P4 | Lucena-1 (vincristine-resistant K562); FEPS (daunorubicin-resistant K562) | [131] |
Y. Enhance SACLAC (acid ceramidase inhibitor) sensitivity | PDMP | HL-60/VCR (vincristine-resistant); HL-60/DNR (daunorubicin-resistant) | [166] |
Z. Enhance hydroxychloroquine or DC661 sensitivity (lysosomal autophagy inhibitors) | Genz-123346 | A375-P (human melanoma cell line); DLD-1 (human colorectal adenocarcinoma cell line); B16-F10 (murine melanoma cell line); MIA PaCa-2; A549; PDXWM4380 and PDX WM4552 (patient-derived cell lines) | [187] |
AA. Reverse sorafenib resistance | PDMP | Hep3B; HepG2 (hepatocellular carcinoma cell lines) | [111] |
AB. Sensitize to cisplatin | PPMP | HN9-cisR (cisplatin-resistant human head and neck cancer cell line) | [127] |
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Ung, J.; Kassai, M.; Tan, S.-F.; Loughran, T.P., Jr.; Feith, D.J.; Cabot, M.C. The Drug Transporter P-Glycoprotein and Its Impact on Ceramide Metabolism—An Unconventional Ally in Cancer Treatment. Int. J. Mol. Sci. 2024, 25, 9825. https://doi.org/10.3390/ijms25189825
Ung J, Kassai M, Tan S-F, Loughran TP Jr., Feith DJ, Cabot MC. The Drug Transporter P-Glycoprotein and Its Impact on Ceramide Metabolism—An Unconventional Ally in Cancer Treatment. International Journal of Molecular Sciences. 2024; 25(18):9825. https://doi.org/10.3390/ijms25189825
Chicago/Turabian StyleUng, Johnson, Miki Kassai, Su-Fern Tan, Thomas P. Loughran, Jr., David J. Feith, and Myles C. Cabot. 2024. "The Drug Transporter P-Glycoprotein and Its Impact on Ceramide Metabolism—An Unconventional Ally in Cancer Treatment" International Journal of Molecular Sciences 25, no. 18: 9825. https://doi.org/10.3390/ijms25189825