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

Biochem Pharmacol. 2017 Nov 15;144:63-77. doi: 10.1016/j.bcp.2017.08.002. Epub 2017 Aug 5.


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.

Keywords: Breast cancer; Immunotoxin; Photochemical internalization; Photodynamic therapy; Reactive oxygen species; Resistance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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


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