Pharmacogenomic and molecular docking studies on the cytotoxicity of the natural steroid wortmannin against multidrug-resistant tumor cells.

Abstract

Wortmannin is a cytotoxic compound derived from the endophytic fungi Fusarium oxysporum, Penicillium wortmannii and Penicillium funiculosum that occurs in many plants, including medicinal herbs. The rationale to develop novel anticancer drugs is the frequent development of tumor resistance to the existing antineoplasic agents. Therefore, it is mandatory to analyze resistance mechanisms of novel drug candidates such as wortmannin as well to bring effective drugs into the clinic that have the potential to bypass or overcome resistance to established drugs and to substantially increase life span of cancer patients. In the present project, we found that P-glycoprotein-overexpressing tumor cells displaying the classical multidrug resistance phenotype toward standard anticancer drugs were not cross-resistant to wortmannin. Furthermore, three point-mutated PIK3CA protein structures revealed similar binding energies to wortmannin than wild-type PIK3CA. This protein is the primary target of wortmannin and part of the PI3K/AKT/mTOR signaling pathway. PIK3CA mutations are known to be associated with worse response to therapy and shortened its activity toward wild-type and mutant PIK3CA with similar efficacy.

• Authors: Victor Kuete, Mohamed E M Saeed, Onat Kadioglu, Jonas Börtzler, Hassan Khalid, Henry Johannes Greten, Thomas Efferth
• Journal: Phytomedicine : international journal of phytotherapy and phytopharmacology (Phytomedicine) Vol. 22 Issue 1 Pg. 120-7 (Jan 15 2015) ISSN: 1618-095X [Electronic] Germany
• PMID: 25636880 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014. Published by Elsevier GmbH.

Chemical References

• ABCB1 protein, human
• ATP Binding Cassette Transporter, Subfamily B
• Androstadienes
• Antineoplastic Agents
• Phosphatidylinositol 3-Kinases
• Class I Phosphatidylinositol 3-Kinases
• PIK3CA protein, human
• Wortmannin

Topics

• ATP Binding Cassette Transporter, Subfamily B (metabolism)
• Androstadienes (pharmacology)
• Antineoplastic Agents (pharmacology)
• Cell Line, Tumor
• Class I Phosphatidylinositol 3-Kinases
• Cluster Analysis
• Drug Resistance, Multiple
• Drug Resistance, Neoplasm (drug effects)
• Humans
• Molecular Docking Simulation
• Oligonucleotide Array Sequence Analysis
• Pharmacogenetics
• Phosphatidylinositol 3-Kinases (metabolism)
• Signal Transduction (drug effects)
• Wortmannin