Dual targeting of microtubule and topoisomerase II by α-carboline derivative YCH337 for tumor proliferation and growth inhibition

Oncotarget. 2015 Apr 20;6(11):8960-73. doi: 10.18632/oncotarget.3264.


Both microtubule and topoisomerase II (Top2) are important anticancer targets and their respective inhibitors are widely used in combination for cancer therapy. However, some combinations could be mutually antagonistic and drug resistance further limits their therapeutic efficacy. Here we report YCH337, a novel α-carboline derivative that targets both microtubule and Top2, eliciting tumor proliferation and growth inhibition and overcoming drug resistance. YCH337 inhibited microtubule polymerization by binding to the colchicine site and subsequently led to mitotic arrest. It also suppressed Top2 and caused DNA double-strand breaks. It disrupted microtubule more potently than Top2. YCH337 induced reversible mitotic arrest at low concentrations but persistent DNA damage. YCH337 caused intrinsic and extrinsic apoptosis and decreased MCL-1, cIAP1 and XIAP proteins. In this aspect, YCH337 behaved differently from the combination of vincristine and etoposide. YCH337 inhibited proliferation of tumor cells with an averaged IC50 of 0.3 μM. It significantly suppressed the growth of HT-29 xenografts in nude mice too. Importantly, YCH337 nearly equally killed different-mechanism-mediated resistant tumor cells and corresponding parent cells. Together with the novelty of its chemical structure, YCH337 could serve as a promising lead for drug development and a prototype for a dual microtubule/Top2 targeting strategy for cancer therapy.

Keywords: YCH337; antitumor activity; microtubule; topoisomerase II; α-carboline derivative.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Binding Sites / drug effects
  • Binding, Competitive
  • Carbolines / pharmacology
  • Carbolines / therapeutic use*
  • Cell Line, Tumor
  • Colchicine / metabolism
  • Colonic Neoplasms / drug therapy
  • DNA Breaks, Double-Stranded / drug effects*
  • DNA Topoisomerases, Type II / physiology
  • DNA, Neoplasm / drug effects*
  • DNA, Superhelical / drug effects
  • Drug Interactions
  • Drug Screening Assays, Antitumor
  • Etoposide / pharmacology
  • Humans
  • Inhibitory Concentration 50
  • Metaphase / drug effects
  • Mice
  • Mice, Nude
  • Microtubules / drug effects
  • Microtubules / metabolism
  • Molecular Structure
  • Neoplasm Proteins / antagonists & inhibitors*
  • Neoplasm Proteins / biosynthesis
  • Neoplasm Proteins / physiology
  • Paclitaxel / pharmacology
  • Topoisomerase II Inhibitors / chemical synthesis
  • Topoisomerase II Inhibitors / pharmacology
  • Topoisomerase II Inhibitors / therapeutic use*
  • Tubulin / metabolism
  • Tubulin Modulators / chemical synthesis
  • Tubulin Modulators / pharmacology
  • Tubulin Modulators / therapeutic use*
  • Vincristine / pharmacology


  • (2-hydroxy-5-methoxyphenyl)(9H-pyrido(2,3-b)indol-3-yl)methanone
  • Carbolines
  • DNA, Neoplasm
  • DNA, Superhelical
  • Neoplasm Proteins
  • Topoisomerase II Inhibitors
  • Tubulin
  • Tubulin Modulators
  • Vincristine
  • Etoposide
  • DNA Topoisomerases, Type II
  • Paclitaxel
  • Colchicine