Taxanes with high potency inducing tubulin assembly overcome tumoural cell resistances |
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| Institution: | 1. Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Ramiro de Maeztu 9, 28040 Madrid, Spain;2. Centro de Estudios Avanzados de Cuba, Carretera San Antonio km 1 1/2, Valle Grande, La Lisa, Ciudad Habana CP 17100, Cuba;3. Institute of Chemical Biology and Drug Discovery, Stony Brook University, Stony Brook, NY 11794-3400, USA;4. Instituto de Estructura de la Materia, Consejo Superior de Investigaciones Científicas IEM-CSIC, Serrano 121, 28006 Madrid, Spain;5. State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, 2A Nan Wei Road Street, Beijing 100050, China;6. Department of Chemistry, Stony Brook University, Stony Brook, NY 11794-3400, USA;1. Inst. of Pharmaceutical Sciences, Eidgenössische Technische Hochschule (ETH) Zürich, Wolfgang-Pauli Strasse 10, Zürich, CH-8093, Switzerland;1. Division of Medical Genetics, Department of Pediatrics, University of Utah, 2C412 SOM, 50 North Mario Capecchi Drive, Salt Lake City, UT 84132, USA;2. Department of Basic Medical Sciences, University of Bari, Piazza Giulio Cesare 11, Policlinico, I-70124 Bari, Italy;3. ARUP Institute for Clinical and Experimental Pathology®, ARUP Laboratories, 500 Chipeta Way, Salt Lake City, UT 84108, USA;4. Department of Pathology, University of Utah, Salt Lake City, UT 84132, USA;1. Center for Liver Cancer, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do, Republic of Korea;2. Department of Surgery, College of Medicine, Kangwon National University, 1 Kangwondaehak-gil, Chuncheon-si, Gangwon-do, 200-701 Republic of Korea;1. X-ray Crystallography Laboratory, Post-Graduate Department of Physics & Electronics, University of Jammu, Jammu Tawi, 180 006, India;2. Laboratory of Natural Products & Organic Synthesis, Department of Chemistry, Visva- Bharati (a Central University), Santiniketan, 731 235, West Bengal, India;3. Department of Physics, University of Lucknow, Lucknow, 226007, Uttar Pradesh, India;4. Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur, 208016, Uttar Pradesh, India;3. From the Department of Pathology and Cancer Research and Treatment Center, University of New Mexico Health Sciences Center, Albuquerque, New Mexico 87131;4. the Department of Clinical Biochemistry, Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, United Kingdom;3. From the Department of Chemistry and Biochemistry, College of Charleston, Charleston, South Carolina 29424;4. the Department of Biochemistry and Nebraska Redox Biology Center, University of Nebraska, Lincoln, Nebraska 68588 |
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| Abstract: | We have found that four taxanes with chemical modifications at positions C10 and C13 were active against all types of taxane resistant cell lines, resistant by P-gp overexpression, by mutations in the β-tubulin binding site or by overexpression of the highly dynamic βIII-tubulin isotype.We have characterized the interaction of taxanes with high activity on chemotherapy resistant tumoural cells with microtubules, and also studied their cellular effects. The biochemical property enhanced in comparison with other taxanes is their potency at inducing tubulin assembly, despite the fact that their interactions with the microtubule binding sites (pore and luminal) are similar as studied by NMR and SAXS. A differential interaction with the S7–S9 loop (M-loop) is responsible for their enhanced assembly induction properties. The chemical changes in the structure also induce changes in the thermodynamic properties of the interaction, indicating a higher hydrophilicity and also explaining their properties on P-gp and βIII overexpressing cells and on mutant cells.The effect of the compounds on the microtubular network is different from those observed with the classical (docetaxel and paclitaxel) taxanes, inducing different bundling in cells with microtubules being very short, indicating a very fast nucleation effect and reflecting their high assembly induction power. |
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| Keywords: | Paclitaxel Microtubules Tubulin Chemotherapy Resistance |
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