posted on 2021-09-15, 23:43authored byBarry
J. Liang, Sabrina Lusvarghi, Suresh V. Ambudkar, Huang-Chiao Huang
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.