For more than two decades, we have studied the unique characteristics of cells resistant to Photodynamic Therapy (PDT) following repeated in vitro treatment sessions. Among the many PDT-resistant cells isolated in our laboratory, we have never found cross-resistance to other photosensitizers (PS) or chemotherapeutic drugs, suggesting the involvement of PS-specific factors rather than general antioxidant defense systems.
Developing a significant level of resistance requires multiple PDT rounds. For example, 10 to 15 cycles of aminolevulinic acid (ALA)-PDT led to a 4 to 7-fold increase in resistance in LM3 murine mammary tumour cells [1], while human mammary Ras-transfected HB4a cells exhibited slight resistance (1.2 to 2-fold) after three successive PDT cycles using different PSs: ALA, Verteporfin, m-THPC, and Merocyanine [2]. However, complete cell killing was achieved by increasing the light dose.
All PDT-resistant cell populations we isolated were less migratory and invasive than their parental counterparts and demonstrated significantly impaired metastatic potential in vivo. Additionally, these cells showed decreased general anchorage-dependent adhesion and invasion, along with disrupted cytoskeletons and altered expression of adhesion proteins.
Interestingly, we have also found that even when Ras-transfected cells present lower adherence to extracellular matrix proteins, this does not make them more sensitive to PDT or chemotherapy. On the contrary, a marked gain of resistance to PDT was observed in floating cells compared to adhesive cells, accounting for the higher ability conferred by Ras to survive in conditions of decreased cell-extracellular matrix interactions [3].
The presence of cancer stem cells (CSCs) has recently been considered a major cause of failure in anticancer therapies. While the current state of the art suggests that successful elimination of CSCs can be achieved after PDT, our studies indicate an enrichment of the stem cell fraction in IGROV-1 ovarian cancer cells after exposure to PDT selective pressure, evidenced by higher OCT4 and NANOG expression and a higher number of sphere formation.
Recently, we found that SKOV-3 and IGROV-1 ovarian cancer cells resistant to cisplatin did not exhibit cross-resistance to PDT. Conversely, PDT-resistant ovarian cancer cells remained responsive to cisplatin and paclitaxel treatments and were equally migratory and invasive compared to the parental cell lines.
The dual action of the photosensitizer and light in PDT, along with the multiple sites of action targeted, makes the development of resistance quite unusual in a clinical setting.