Dual-targeting antitumor conjugates derived from platinum(IV) prodrugs and microtubule inhibitor CA-4 significantly exhibited potent ability to overcome cisplatin resistance |
| |
| Affiliation: | 1. Institute of Biophysics, Academy of Sciences of the Czech Republic, v.v.i., Kralovopolska 135, CZ-61265 Brno, Czech Republic;2. Department of Biophysics, Faculty of Science, Palacky University, 17. listopadu 12, CZ-77146 Olomouc, Czech Republic;3. Institute for Drug Research, School of Pharmacy, The Hebrew University, Jerusalem 91120, Israel;1. Institute for Biological Research “Siniša Stanković”, University of Belgrade, Despota Stefana 142, 11060 Belgrade, Serbia;2. BioLab, Instituto Universitario de Bio-Organica “Antonio Gonzalez” (IUBO-AG), Centro de Investigaciones Biomédicas de Canarias (CIBICAN), Universidad de La Laguna, Avda. Astrofisico Francisco Sánchez 2, 38206 La Laguna, Tenerife, Spain;3. Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Vojvode Stepe 444a, PO BOX 23, 11010 Belgrade, Serbia;1. Institute of Biophysics, Academy of Sciences of the Czech Republic, v.v.i., Kralovopolska 135, CZ-61265 Brno, Czech Republic;2. Department of Biophysics, Faculty of Science, Palacky University, 17. listopadu 12, CZ-77146 Olomouc, Czech Republic;3. Institute for Drug Research, School of Pharmacy, The Hebrew University, Jerusalem 91120, Israel |
| |
| Abstract: | Here we report that three platinum(IV) prodrugs containing a tubulin inhibitor CA-4, as dual-targeting platinum(IV) prodrug, were synthesized and evaluated for antitumor activity using MTT assay. Among them, complex 9 exhibited the most potent antitumor activity against the tested cancer lines including cisplatin resistance cancer cells, and simultaneously displayed lower toxicity compared to cisplatin, respectively. Moreover, complex 9, in which was conjugated to an inhibitor of tubulin at one axial position of platinum(IV) complex, could effectively enter the cancer cells, and significantly induce cell apoptosis and arrest the cell cycle in A549 cells at G2/M stage, and dramatically disrupt the microtubule organization. In addition, mechanism studies suggested that complex 9 significantly induced reactive oxygen species (ROS) generation and decreased mitochondrial trans-membrane potential (MMP) in A549 cells, and effectively induced activation of caspases triggering apoptotic signaling through mitochondrial dependent apoptosis pathways. |
| |
| Keywords: | Platinum(IV) prodrugs Antitumor activity CA-4 Apoptosis |
| 本文献已被 ScienceDirect 等数据库收录！ |
|
