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Synthetic Peroxides Promote Apoptosis of Cancer Cells by Inhibiting P-Glycoprotein ABCB5 |
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| Authors: | Dr Ivan A Yaremenko Dr Paolo Coghi Parichat Prommana Congling Qiu Peter S Radulov Yuanqing Qu Yulia Yu Belyakova Dr Enrico Zanforlin Dr Vladimir A Kokorekin Yuki Yu Jun Wu Prof Fabrice Fleury Dr Chairat Uthaipibull Dr Vincent Kam Wai Wong Prof Alexander O Terent'ev |
| Affiliation: | 1. N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky Prospect 47, Moscow, 119991 Russia
These authors contributed equally;2. School of Pharmacy, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macau, China These authors contributed equally;3. National Center for Genetic Engineering and Biotechnology (BIOTEC), National Science and Technology Development Agency (NSTDA), 113 Thailand Science Park, Pathum Thani, 12120 Thailand;4. State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macau, China;5. N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky Prospect 47, Moscow, 119991 Russia;6. Department of Pharmaceutical and Pharmacological Sciences, University of Padova, via Marzolo 5, 35131 Padova, Italy;7. Mechanism and Regulation of DNA Repair Team UFIP CNRS UMR 6286, Université de Nantes, 2 chemin de la Houssinière, 44322 Nantes, France |
| Abstract: | This article discloses a new horizon for the application of peroxides in medical chemistry. Stable cyclic peroxides are demonstrated to have cytotoxic activity against cancer cells; in addition a mechanism of cytotoxic action is proposed. Synthetic bridged 1,2,4,5-tetraoxanes and ozonides were effective against HepG2 cancer cells and some ozonides selectively targeted liver cancer cells (the selectivity indexes for compounds 11 b and 12 a are 8 and 5, respectively). In some cases, tetraoxanes and ozonides were more selective than paclitaxel, artemisinin, and artesunic acid. Annexin V flow-cytometry analysis revealed that the active ozonides 22 a and 23 a induced cell death of HepG2 by apoptosis. Further study showed that compounds 22 a and 23 a exhibited a strong inhibitory effect on P-glycoprotein (P-gp/ABCB5)-overexpressing HepG2 cancer cells. ABCB5 is a key player in the multidrug-resistant phenotype of liver cancer. Peroxides failed to demonstrate a direct correlation between oxidative potential and their biological activity. To our knowledge this is the first time that peroxide diastereoisomers have been found to show stereospecific antimalarial action against the chloroquine-sensitive 3D7 strain of Plasmodium falciparum. Stereoisomeric ozonide 12 b is 11 times more active than stereoisomeric ozonide 12 a (IC50=5.81 vs 65.18 μm ). Current findings mean that ozonides merit further investigation as potential therapeutic agents for drug-resistant hepatocellular carcinoma. |
| Keywords: | apoptosis cancer cytotoxicity HepG2 malaria ozonide peroxides tetraoxane |
