Photodynamic therapy of multidrug resistant leukemic murine cells by 3,6-bis(alkylthiourea)acridine hydrochlorides
Helena Paulíková1, Alžbeta Cisáriková1, Zuzana Bačová2
1Department of Biochemistry and Microbiology, Faculty of Chemical and Food Technology, Slovak University of Technology, Bratislava, Slovakia.
Abstract:
Efforts to overcome multidrug resistance in cancer have led to the development of several novel strategies including photodynamic therapy (PDT). PDT is based on the use of photosensitizers (PSs) photoactivation, which causes the formation of reactive oxygen species that can induce cell death. In the last decade, the development of new PSs has been significantly accelerated. Recently, acridine-3,6-dialkyldithiourea hydrochlorides (AcrDTUs) have been investigated as a new group of PSs and we have shown that PDT/AcrDTUs caused cell death of mouse leukemic cells L1210. In this study, we investigated the efficacy of PDT/AcrDTUs for the treatment of L1210/VCR cells as a model of chemoresistant cells (overexpressing P-glycoprotein, P-gp). The photoactivation (365 nm, 1.05 J/cm2) increased the cytotoxicity of AcrDTUs 10-15 times. Inhibition of P-gp (verapamil) has been shown to have no significant effect on the accumulation of propyl-AcrDTU (the most potent derivative) in L1210/VCR cells. The intracellular distribution of this acridine derivative has been studied. Prior to irradiation of the resistant cells, propyl-AcrDTU was sequestered mainly in the cytosol, partly in the mitochondria, and, unlike in the sensitive cells, the AcrDTU was not found in the lysosomes. PDT with 1 µM propyl-AcrDTU induced cell shrinkage and "ladder DNA" formation, and although a drastic decrease of the intracellular ATP level was observed at the same time, there was no increase in extracellular LDH activity. AIF in the nucleus can induce DNA fragmentation and we have actually observed a mitochondrio-nuclear translocation of AIF. We concluded that AcrDTUs are photocytotoxic against L1210/VCR cells and that mitochondria play an important role in cell death induced by PDT.
Insights
Photodynamic therapy using acridine-3,6-dialkyldithiourea hydrochlorides (AcrDTUs) effectively kills multidrug-resistant cancer cells. This novel approach targets chemoresistant cells by inducing cell death pathways involving mitochondria.
Area of Science:
- Biochemistry
- Cancer Research
- Photochemistry
Background:
- Multidrug resistance (MDR) in cancer necessitates novel therapeutic strategies.
- Photodynamic therapy (PDT) utilizes photosensitizers (PSs) to generate reactive oxygen species, inducing cell death.
- Acridine-3,6-dialkyldithiourea hydrochlorides (AcrDTUs) represent a new class of PSs investigated for cancer treatment.
Purpose of the Study:
- To evaluate the efficacy of PDT with AcrDTUs against chemoresistant L1210/VCR cells, which overexpress P-glycoprotein (P-gp).
- To investigate the mechanism of cell death induced by PDT/AcrDTUs in these resistant cells.
Main Methods:
- Treatment of L1210/VCR cells with propyl-AcrDTU followed by photoactivation at 365 nm.
- Assessment of P-gp inhibition effects using verapamil.
- Analysis of intracellular distribution of propyl-AcrDTU, cell morphology, DNA fragmentation, ATP levels, and AIF translocation.
Main Results:
- Photoactivation significantly increased AcrDTU cytotoxicity (10-15 times) against L1210/VCR cells.
- Propyl-AcrDTU accumulated in the cytosol and mitochondria, but not lysosomes, of resistant cells.
- PDT induced cell shrinkage, DNA fragmentation, decreased ATP levels, and mitochondrio-nuclear translocation of AIF.
Conclusions:
- AcrDTUs exhibit photocytotoxicity against multidrug-resistant L1210/VCR cells.
- Mitochondria play a crucial role in the cell death pathway initiated by PDT with AcrDTUs.
- PDT/AcrDTUs represent a promising strategy for overcoming chemoresistance in cancer.
