Mechanistic Insights into Photodynamic Regulation of Adenosine 5′-Triphosphate-Binding Cassette Drug Transporters

Abstract

Efforts to overcome cancer multidrug resistance through inhibition of the adenosine triphosphate-binding cassette (ABC) drug transporters ABCB1 and ABCG2 have largely failed in the clinic. The challenges faced during the development of non-toxic modulators suggest a need for a conceptual shift to new strategies for the inhibition of ABC drug transporters. Here, we reveal the fundamental mechanisms by which photodynamic therapy (PDT) can be exploited to manipulate the function and integrity of ABC drug transporters. PDT is a clinically relevant, photochemistry-based tool that involves the light activation of photosensitizers to generate reactive oxygen species. ATPase activity and in silico molecular docking analyses show that the photosensitizer benzoporphyrin derivative (BPD) binds to ABCB1 and ABCG2 with micromolar half-maximal inhibitory concentrations in the absence of light. Light activation of BPD generates singlet oxygen to further reduce the ATPase activity of ABCB1 and ABCG2 by up to 12-fold in an optical dose-dependent manner. Gel electrophoresis and Western blotting revealed that light-activated BPD induces the aggregation of these transporters by covalent cross-linking. We provide a proof of principle that PDT affects the function of ABCB1 and ABCG2 by modulating the ATPase activity and protein integrity of these transporters. Insights gained from this study concerning the photodynamic manipulation of ABC drug transporters could aid in the development and application of new optical tools to overcome the multidrug resistance that often develops after cancer chemotherapy.

Co-Packaged PARP inhibitor and photosensitizer for targeted photo-chemotherapy of 3D ovarian cancer spheroids

“…In contrast, treatments with PIC, PIC + NP-Tal, or PIC-NP-Tal at 20 and 50 J/cm 2 reduced the viability of chemo-sensitive cancer cells, but they did not effectively control the chemo-resistant cells. These results are consistent with our previous findings [ 26 – 28 ], showing that PDT using light-activated BPD mitigates chemo-selection pressure. Further mechanistic studies of the role of PIC-based photoimmunotherapy in modulating chemo-selection pressure in vitro and in vivo are needed.…”

Chemophototherapeutic Ablation of Doxorubicin‐Resistant Human Ovarian Tumor Cells†

“…More significantly, we have previously demonstrated that the main mechanism of LC‐Dox‐PoP is to increase drug delivery to solid tumors following permeabilization of tumor vasculature (19), a phenomenon which is generally not straightforward to observe in vitro . However, some studies have shown that enhancement in drug delivery can be achieved in vitro when drug efflux pumps are directly affected during the PDT process (20). For the Dox‐resistant human ovarian A2780‐R cancer cell line used in this research study, although less Dox is uptaken by these cells compared to the nonresistant parental line (21), P‐gp was not found to be upregulated and the resistant mechanism has been proposed to involve glutathione‐mediated drug modification (22).…”

Phenylspirodrimane with Moderate Reversal Effect of Multidrug Resistance Isolated from the Deep-Sea Fungus Stachybotrys sp. 3A00409

“…Molecule docking simulation technology is a convenient and effective method to explore the interaction between small molecules and targets [32][33][34][35]. We performed a molecular docking simulation to characterize the molecular basis of the interactions between compound 8 and the human homology model of the ABCB1 transporter protein structure (PDB ID: 6QEX).…”