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.
Highlights
Combination chemotherapy for the treatment of cancer was introduced approximately 50 years ago [1, 2]
These results 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 poly ADP ribose polymerase (PARP) inhibitor
The liposomal nanoparticles (OLICARB) containing encapsulated combinations of olaparib and carboplatin at the ratio of their molar concentrations of 1:1 and 2:1 (OLICARB1:1 and OLICARB2:1, respectively) were characterized by inductively coupled plasma mass spectrometry (ICP-MS) or flameless atomic absorption spectrometry (FAAS) for platinum content, UV absorption spectrophotometry for olaparib content; the phosphate analysis for the phospholipid content was performed by ICP-MS
Summary
Combination chemotherapy for the treatment of cancer was introduced approximately 50 years ago [1, 2]. The rationale for combination chemotherapy is to use drugs that work by different mechanisms, thereby decreasing the likelihood that resistant cancer cells will develop. Combining metal- and organic-based drugs to increase therapeutic efficacy over single drug treatments, that is to produce a synergistic effect, has the potential to aid in overcoming resistance by targeting different mechanisms of action [5]. This therapeutic approach has significant implications for metallodrugs. The results of related preclinical testing [8,9,10,11] demonstrated increased antitumor activity of platinum drugs combined with inhibition of the enzyme poly ADP ribose polymerase (PARP) pointing to a role of PARP proteins in the repair of DNA damaged by platinum antitumor drugs
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