Oncotarget

Research Papers:

This article has been corrected. Correction in: Oncotarget. 2018; 9:35599.

Simultaneous delivery of olaparib and carboplatin in PEGylated liposomes imparts this drug combination hypersensitivity and selectivity for breast tumor cells

Vojtech Novohradsky, Juraj Zajac, Oldrich Vrana, Jana Kasparkova and Viktor Brabec _

PDF  |  HTML  |  Supplementary Files  |  How to cite  |  Order a Reprint

Oncotarget. 2018; 9:28456-28473. https://doi.org/10.18632/oncotarget.25466

Metrics: PDF 463 views  |   HTML 800 views  |   ?  


Abstract

Vojtech Novohradsky1, Juraj Zajac1, Oldrich Vrana1, Jana Kasparkova1 and Viktor Brabec1

1Institute of Biophysics, Czech Academy of Sciences, Kralovopolska 135, CZ-61265 Brno, Czech Republic

Correspondence to:

Viktor Brabec, email: brabec@ibp.cz

Keywords: olaparib; carboplatin; combination; liposomes; antitumor activity

Received: December 01, 2017     Accepted: May 05, 2018     Published: June 19, 2018

ABSTRACT

Combination regiments involving platinum anticancer drugs and agents with unrelated mechanisms of action are a subject of widespread interest.

Here, we show that synergistic toxic action in cancer cells of combinations of antitumor platinum drug carboplatin and effective PARP inhibitor olaparib is considerably improved if these combined drugs are encapsulated into liposomes. Notably, the formation of such nano-formulations, called OLICARB, leads to a marked enhancement of activity in human cancer cell lines (including those resistant to conventional platinum antitumor drugs) and selectivity towards tumor cells. We used immunofluorescence analysis of γH2AX expression and examined DNA damage in cancerous cells treated with the investigated compounds. We find that the synergistic toxic effects in cancer cells of both drugs used in combination, nonencapsulated or embedded in the OLICARB nanoparticles, positively correlates with DNA damage. These results also suggest that the enhancement of the toxic effects of carboplatin by olaparib in cancer cells is a consequence of an accumulation of cytotoxic lesions in DNA due to the inhibition of repair of platinated DNA augmented by the synergistic action of olaparib as an effective PARP inhibitor. Our findings also reveal that the combination of olaparib with carboplatin encapsulated in the OLICARB nanoparticles is particularly effective to inhibit the growth of 3D mammospheres. Collectively, the data provide convincing evidence that the encapsulation of carboplatin and olaparib into liposomal constructs to form the OLICARB nanoparticles may represent the viable approach for the treatment of tumors with the aim to eliminate the possible effects of acquired resistance.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 25466