Evolutionary dynamics of cancer multidrug resistance in response to olaparib and photodynamic therapy

Autor: Yan Baglo, Aaron J. Sorrin, Cindy Liu, Jocelyn Reader, Dana M. Roque, Huang-Chiao Huang, Xiaocong Pu
Rok vydání: 2021
Předmět:
Cancer Research
NCI/ADR-RES-EGFP
Multidrug resistant OVCAR-8 subline overexpressing P-gp and enhanced green fluorescent protein
medicine.medical_treatment
Population
Photodynamic therapy
Multidrug resistance
Poly (ADP-Ribose) Polymerase Inhibitor
Cancer evolution
Olaparib
DNA
Deoxyribonucleic acid
chemistry.chemical_compound
P-gp
P-glycoprotein
Medicine
Photosensitizer
PDT
Photodynamic therapy
SF
Survival fraction
education
RC254-282
Original Research
PE
Plating efficiency
education.field_of_study
business.industry
ABC
ATP-binding cassette
Neoplasms. Tumors. Oncology. Including cancer and carcinogens
DMSO
Dimethyl sulfoxide
Cancer
ATP-binding cassette transporters
(16:0)LysoPC
1-palmitoyl-2-hydroxy-sn-glycero-3-phosphocholine
medicine.disease
FACS
Fluorescence-activated cell sorting
PBS
Phosphate-buffered saline
BPD
Benzoporphyrin derivative
ANOVA
One-way analysis of variance
Poly (ADP-ribose) polymerase inhibitors
Multiple drug resistance
MDR
Multidrug resistance
FDA
U.S. Food and Drug Administration
Oncology
chemistry
TBST
Tris-buffered saline with 0.1% Tween® 20 Detergent
Cancer cell
Cancer research
RIPA buffer
Radioimmunoprecipitation assay buffer
ATP
Adenosine triphosphate
business
OVCAR-8-DsRed2
Human ovarian cancer cell line OVCAR-8 expressing Discosoma sp. red fluorescent protein
PARP
Poly(ADP-ribose) polymerase
ROS
Reactive oxygen species
Zdroj: Translational Oncology
Translational Oncology, Vol 14, Iss 11, Pp 101198-(2021)
ISSN: 1936-5233
DOI: 10.1016/j.tranon.2021.101198
Popis: Highlights • Combination of olaparib and photodynamic therapy is effective in reducing the number and clonogenic survival of ovarian cancer cells. • Photodynamic therapy using a lipidated photosensitizer reduces the selective advantage of olaparib-resistant ovarian cancer cells. • Photodynamic therapy potentiates the DNA-damaging effects of olaparib.
P-glycoprotein (P-gp) is an adenosine triphosphate (ATP)-dependent drug efflux protein commonly associated with multidrug resistance in cancer chemotherapy. In this report, we used a dual-fluorescent co-culture model to study the population dynamics of the drug sensitive human ovarian cancer cell line (OVCAR-8-DsRed2) and its resistant subline that overexpresses P-gp (NCI/ADR-RES-EGFP) during the course of a photodynamic therapy (PDT)-olaparib combination regimen. Without treatment, OVCAR-8-DsRed2 cells grew more rapidly than the NCI/ADR-RES-EGFP cells. Olaparib treatment reduced the total number of cancer cells by 70±4% but selected for the resistant NCI/ADR-RES-EGFP population since olaparib is an efflux substrate for the P-gp pump. This study used the FDA-approved benzoporphyrin derivative (BPD) photosensitizer or its lipidated formulation ((16:0)LysoPC-BPD) to kill OVCAR-8 cells and reduce the likelihood that olaparib-resistant cells would have selective advantage. Three cycles of PDT effectively reduced the total cell number by 66±3%, while stabilizing the population ratio of sensitive and resistant cells at approximately 1:1. The combination of olaparib treatment and PDT enhanced PARP cleavage and deoxyribonucleic acid (DNA) damage, further decreasing the total cancer cell number down to 10±2%. We also showed that the combination of olaparib and (16:0)LysoPC-BPD-based PDT is up to 18-fold more effective in mitigating the selection of resistant NCI/ADR-RES-EGFP cells, compared to using olaparib and BPD-based PDT. These studies suggest that PDT may improve the effectiveness of olaparib, and the use of a lipidated photosensitizer formulation holds promise in overcoming cancer drug resistance.
Databáze: OpenAIRE
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