Breaking the Iron Homeostasis: A “Trojan Horse” Self-Assembled Nanodrug Sensitizes Homologous Recombination Proficient Ovarian Cancer Cells to PARP Inhibition

Poly­(adenosine diphosphate-ribose) polymerase (PARP) inhibitors are used in ovarian cancer treatment and have greatly improved the survival rates for homologous recombination repair (HRR)-deficient patients. However, their therapeutic efficacy is limited in HRR-proficient ovarian cancer. Thus, sens...

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Published in:ACS nano 2022-08, Vol.16 (8), p.12786-12800
Main Authors: Li, Yangyang, Cen, Yixuan, Fang, Yifeng, Tang, Sangsang, Li, Sen, Ren, Yan, Zhang, Hongbo, Lu, Weiguo, Xu, Junfen
Format: Article
Language:English
Subjects:
Apoptosis
Carcinoma, Ovarian Epithelial - drug therapy
Cell Line, Tumor
Female
Homeostasis
Homologous Recombination
Humans
Iron - pharmacology
Nanoparticles - therapeutic use
Ovarian Neoplasms - drug therapy
Ovarian Neoplasms - pathology
Phosphatidylinositol 3-Kinases - genetics
Poly(ADP-ribose) Polymerase Inhibitors - pharmacology
Poly(ADP-ribose) Polymerases - genetics
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Summary:Poly­(adenosine diphosphate-ribose) polymerase (PARP) inhibitors are used in ovarian cancer treatment and have greatly improved the survival rates for homologous recombination repair (HRR)-deficient patients. However, their therapeutic efficacy is limited in HRR-proficient ovarian cancer. Thus, sensitizing HRR-proficient ovarian cancer cells to PARP inhibitors is important in clinical practice. Here, a nanodrug, olaparib-Ga, was designed using self-assembly of the PARP inhibitor olaparib into bovine serum albumin through gallic acid gallium­(III) coordination via a convenient and green synthetic method. Compared with olaparib, olaparib-Ga featured an ultrasmall size of 7 nm and led to increased suppression of cell viability, induction of DNA damage, and enhanced cell apoptosis in the SKOV3 and OVCAR3 HRR-proficient ovarian cancer cells in vitro. Further experiments indicated that the olaparib-Ga nanodrug could suppress RRM2 expression, activate the Fe2+/ROS/MAPK pathway and HMOX1 signaling, inhibit the PI3K/AKT signaling pathway, and enhance the expression of cleaved-caspase 3 and BAX protein. This, in turn, led to increased cell apoptosis in HRR-proficient ovarian cancer cells. Moreover, olaparib-Ga effectively restrained SKOV3 and OVCAR3 tumor growth and exhibited negligible toxicity in vivo. In conclusion, we propose that olaparib-Ga can act as a promising nanodrug for the treatment of HRR-proficient ovarian cancer.
ISSN:1936-0851
1936-086X
DOI:10.1021/acsnano.2c04956