Abstract
Drug combinations are extensively used to treat cancer and are often selected according to complementary mechanisms. Here, we describe a cell-based high-throughput screening assay for identification of synergistic combinations between broadly applied platinum-based chemotherapeutics and drugs from a library composed of 1280 chemically and pharmacologically diverse (mostly FDA approved) compounds. The assay was performed on chemoresistant cell lines derived from lung (A549) and pancreatic (PANC-1) carcinoma, where platinum-based combination regimens are currently applied though with limited success. The synergistic combinations identified during the screening were validated by synergy quantification using the combination index method and via high content fluorescent microscopy analysis. New promising synergistic combinations discovered using this approach include compounds currently not used as anticancer drugs, such as cisplatin or carboplatin with hycanthone and cisplatin with spironolactone in pancreatic carcinoma, and carboplatin and deferoxamine in non-small cell lung cancer. Strong synergy between cisplatin or carboplatin and topotecan in PANC-1 cells, compared to A549 cells, suggests that this combination, currently used in lung cancer treatment regimens, could be applied to pancreatic carcinoma as well. Several drugs used to treat diseases other than cancer, including pyrvinium pamoate, auranofin, terfenadine and haloprogin, showed strong cytotoxicity on their own and synergistic interactions with platinum drugs. This study demonstrates that non-obvious drug combinations that would not be selected based on complementary mechanisms can be identified via high-throughput screening.
Highlights
The subset of non-small cell lung cancer (NSCLC) responding to this treatment is small, the results demonstrate that improvements can be made by tailoring therapy in a cancer type specific manner [24,25]
The PCL compounds are screened alone and in combination with cisplatin, carboplatin or oxaliplatin (Fig 1), at concentrations chosen to correspond to their IC50 and IC20 values
As drug combinations and synergy determination can be problematic, screening was followed by hit confirmation and validation procedures, including synergy quantification and High Content Analysis (HCA)
Summary
One of the leading causes of death, is a term used to describe a large group of related diseases featuring over 100 subtypes, which differ significantly in terms of incidence, mortality. The clinically used platinum-based drugs are neutral Pt(II) complexes with a cis square planar geometry bearing so-called carrier ligands (i.e. two ammines or chelating diamine) and leaving groups (two chlorides or chelating dicarboxylate) [7,14,15,16] Their mechanism of action includes intracellular activation by aquation and subsequent covalent binding to DNA bases, which primarily leads to cell death by apoptosis [7,15]. We have further expanded our methodology with the aim of identifying drug-like molecules that can synergistically potentiate the cytotoxic effects of clinically applied Pt drugs (see Fig 1) against cancers with poor prognosis This is of particular utility, as anticancer chemotherapies typically employ drug cocktails, rather than a single agent. The methodology presented has considerable potential for optimizing Pt drug anticancer therapy including the possibility to obtain new combination treatments for chemoresistant cancers
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