Development of resistance to photodynamic therapy (PDT) in human breast cancer cells is photosensitizer-dependent: Possible mechanisms and approaches for overcoming PDT-resistance.

Abstract

Here we report on the induction of resistance to photodynamic therapy (PDT) in the ABCG2-high human breast cancer cell line MA11 after repetitive PDT, using either Pheophorbide A (PhA) or di-sulphonated meso-tetraphenylchlorin (TPCS2a) as photosensitizer. Resistance to PhA-PDT was associated with enhanced expression of the efflux pump ABCG2. TPCS2a-PDT-resistance was neither found to correspond with lower TPCS2a-accumulation nor reduced generation of reactive oxygen species (ROS). Cross-resistance to chemotherapy (doxorubicin) or radiotherapy was not observed. TPCS2a-PDT-resistant cells acquired a higher proliferation capacity and an enhanced expression of EGFR and ERK1/2. p38 MAPK was found to be a death-signalling pathway in the MA11 cells post TPCS2a-PDT, contrasting the MA11/TR cells in which PDT generated a sustained phosphorylation of p38 that had lost its death-mediated signalling, and an abrogated activation of its downstream effector MAPKAPK2. No difference in apoptosis, necrosis or autophagy responses was found between the treated cell lines. Development of TPCS2a-PDT resistance in the MDA-MB-231 cell line was also established, however, p38 MAPK did not play a role in the PDT-resistance. MCF-7 cells did not develop TPCS2a-PDT-resistance. Photochemical internalisation (PCI) of 1 pM of EGF-saporin induced equal strong cytotoxicity in both MA11 and MA11/TR cells. In conclusion, loss of p38 MAPK-inducing death signalling is the main mechanism of resistance to TPCS2a-PDT in the MA11/TR cell line. This work provides mechanistic knowledge of intrinsic and acquired PDT-resistance which is dependent on choice of photosensitizer, and suggests PCI as a rational therapeutic intervention for the elimination of PDT-resistant cells.

• Authors: Cathrine Elisabeth Olsen, Anette Weyergang, Victoria Tudor Edwards, Kristian Berg, Andreas Brech, Sabine Weisheit, Anders Høgset, Pål Kristian Selbo
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 144 Pg. 63-77 (11 15 2017) ISSN: 1873-2968 [Electronic] England
• PMID: 28784290 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2017 Elsevier Inc. All rights reserved.

Chemical References

• Photosensitizing Agents
• Porphyrins
• meso-tetraphenyl chlorin disulphonate
• Chlorophyll
• p38 Mitogen-Activated Protein Kinases
• pheophorbide a

Topics

• Cell Line, Tumor
• Cell Survival (drug effects, physiology)
• Chlorophyll (analogs & derivatives, pharmacology)
• Drug Resistance, Neoplasm (drug effects, physiology)
• Female
• Humans
• MCF-7 Cells
• Photochemotherapy (methods)
• Photosensitizing Agents (pharmacology)
• Porphyrins (pharmacology)
• p38 Mitogen-Activated Protein Kinases (biosynthesis)