Design, synthesis and antineoplastic activity of novel hybrids of podophyllotoxin and indirubin against human leukaemia cancer cells as multifunctional anti-MDR agents.

Abstract

To overcome cancer drug resistance, in present study, a series of podophyllotoxin-indirubin hybrids were designed, synthesized, and evaluated for anticancer efficacy against two human chronic myeloid leukemia cell cultures. Among them, compound Da-1 was the most potent in resistent K562/VCR cells with an IC50 value of 0.076 ± 0.008 μM. Preliminary mechanism studies showed that Da-1 significantly induced apoptosis and cell cycle arrest at the G2 phase. Decrease in mitochondrial membrane potential, accompanied by activated PARP cleavage, was observed in K562/VCR cells after incubation with Da-1. Meanwhile, Da-1 caused the accumulation of intracellular ROS, regulated JNK and AKT signaling, and down-regulated the expression levels of P-gp and MRP1 proteins. Importantly, Western blotting revealed that Da-1 could induce K562/VCR cells autophagy, by increasing the levels of Beclin1 and LC3-II. Finally, Da-1 could disrupt microtubule organization, and binding mode to tubulin was investigated by using molecular modeling. Together, Da-1 was a novel hybrid with potent antiproliferative activity and might be a promising agent for the treatment of drug-resistant leukemia cancer.

• Authors: Jing Wang, Li Long, Yongzheng Chen, Yingshu Xu, Lei Zhang
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 28 Issue 10 Pg. 1817-1824 (06 01 2018) ISSN: 1464-3405 [Electronic] England
• PMID: 29678463 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier Ltd. All rights reserved.

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Antineoplastic Agents
• Indoles
• Multidrug Resistance-Associated Proteins
• Tubulin
• Proto-Oncogene Proteins c-akt
• JNK Mitogen-Activated Protein Kinases
• Podophyllotoxin
• indirubin
• multidrug resistance-associated protein 1

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (metabolism)
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Apoptosis (drug effects)
• Binding Sites
• Down-Regulation (drug effects)
• Drug Design
• Drug Resistance, Neoplasm (drug effects)
• G2 Phase Cell Cycle Checkpoints (drug effects)
• Humans
• Indoles (chemistry)
• JNK Mitogen-Activated Protein Kinases (metabolism)
• K562 Cells
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive (metabolism, pathology)
• Molecular Dynamics Simulation
• Multidrug Resistance-Associated Proteins (metabolism)
• Podophyllotoxin (chemistry)
• Protein Structure, Tertiary
• Proto-Oncogene Proteins c-akt (metabolism)
• Signal Transduction (drug effects)
• Tubulin (chemistry, metabolism)