Tumor cell lines resistant to ALA-mediated photodynamic therapy and possible tools to target surviving cells
Adriana Casas1, Christian Perotti, Bernhard Ortel
1Centro de Investigaciones sobre Porfirinas y Porfirias (CIPYP), (1056) Ciudad de Buenos Aires, Argentina. adriana@qb.fcen.uba.ar
Abstract:
We isolated and characterized cell lines resistant to aminolevulinic acid (ALA)-mediated photodynamic therapy (PDT) derived from a murine adenocarcinoma and studied cross resistance with other injuries. The most resistant clones were numbers 4 and 8, which exhibited 6.7- and 4.2-fold increase in resistance respectively. Several characteristics were altered in these clones. A 2-fold increase in cell volume, higher cell spreading, and a more fibroblastic, dendritic pattern, were the morphology features that led us to think they could have different adhesive, invasive or metastatic phenotypes. The amount of porphyrins synthesized per cell in the resistant clones was similar to the parental line but, when it was expressed per mg protein, there was a 2-fold decrease, with a higher proportion of hydrophilic porphyrins. These cells were not cross-resistant to photosensitization with Benzoporphyrin derivative and Merocyanine 540, but exhibited a slight resistance to exogenous protoporphyrin IX treatment. Both clones displayed higher protein content and increased number of mitochondria, together with a higher oxygen consumption. The distinctive features found in the resistant lines led as to think how to exploit the changes induced by PDT treatment to target surviving cells. Those hypoxic cells can be also a preferential target of bioreductive drugs and hypoxia-directed gene therapy, and would be sensitive to treatment with other photosensitizers.
Insights
Researchers developed cell lines resistant to aminolevulinic acid (ALA)-photodynamic therapy (PDT). These resistant cells exhibit altered morphology and metabolism, suggesting new therapeutic targets for cancer treatment.
Area of Science:
- Oncology
- Photodynamic Therapy
- Cell Biology
Background:
- Photodynamic therapy (PDT) using aminolevulinic acid (ALA) is a cancer treatment.
- Understanding resistance mechanisms is crucial for improving PDT efficacy.
- Murine adenocarcinoma models provide insights into cancer cell behavior.
Purpose of the Study:
- To isolate and characterize cell lines resistant to ALA-PDT.
- To investigate cross-resistance patterns with other cellular injuries.
- To identify potential therapeutic targets based on resistance mechanisms.
Main Methods:
- Isolation and characterization of ALA-PDT resistant murine adenocarcinoma cell lines (clones 4 and 8).
- Morphological analysis, including cell volume and spreading.
- Biochemical assays to quantify porphyrin synthesis and protein content.
- Mitochondrial activity and oxygen consumption measurements.
- Cross-resistance studies with other photosensitizers and treatments.
Main Results:
- Clones 4 and 8 showed significant resistance (6.7-fold and 4.2-fold) to ALA-PDT.
- Resistant cells exhibited increased volume, spreading, and a fibroblastic/dendritic morphology.
- Porphyrin synthesis per cell was similar, but decreased per mg protein, with a higher proportion of hydrophilic porphyrins.
- No cross-resistance to Benzoporphyrin derivative or Merocyanine 540, but slight resistance to protoporphyrin IX.
- Resistant cells had higher protein content, more mitochondria, and increased oxygen consumption.
Conclusions:
- ALA-PDT resistant cell lines display distinct morphological and metabolic alterations.
- These changes suggest potential roles in adhesion, invasion, and metastasis.
- The altered cellular characteristics, including hypoxia, offer potential targets for novel therapeutic strategies.
- Exploiting these features could enhance treatment efficacy for resistant tumors.
Related Concept Videos
02:57Targeted Cancer Therapies
There are several types of targeted therapies against specific...
02:56Treatment Resistant Cancers
01:27Tumor Immunotherapy