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

6533b870fe1ef96bd12cfd7f

RESEARCH PRODUCT

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

Henry Johannes Greten Mohamed E.m. Saeed Victor Kuete Jonas Börtzler Hassan S. Khalid Thomas Efferth Onat Kadioglu

subject

Drug ATP Binding Cassette Transporter Subfamily B Class I Phosphatidylinositol 3-Kinases media_common.quotation_subject Pharmaceutical Science Antineoplastic Agents ATP-binding cassette transporter Drug resistance Pharmacology Biology Wortmannin Phosphatidylinositol 3-Kinases chemistry.chemical_compound Cell Line Tumor Drug Discovery Cluster Analysis Humans Cytotoxicity Protein kinase B PI3K/AKT/mTOR pathway Oligonucleotide Array Sequence Analysis media_common Pharmacology Drug Resistance Multiple Androstadienes Molecular Docking Simulation Multiple drug resistance Complementary and alternative medicine chemistry Drug Resistance Neoplasm Pharmacogenetics Molecular Medicine Wortmannin Signal Transduction

description

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.

year	journal	country	edition	language
2014-10-01	Phytomedicine

https://doi.org/10.1016/j.phymed.2014.11.011