A novel indolocarbazole, ICP-1, abrogates DNA damage-induced cell cycle arrest and enhances cytotoxicity: similarities and differences to the cell cycle checkpoint abrogator UCN-01

Mol Cancer Ther. 2002 Oct;1(12):1067-78.


DNA damaging agents such as cisplatin arrest cell cycle progression at either G1, S, or G2 phase, although the G1 arrest is only seen in cells expressing the wild-type p53 tumor suppressor protein. We have reported that 7-hydroxystaurosporine (UCN-01) overcomes S and G2 phase arrest and enhances the cytotoxicity of cisplatin. Abrogation of arrest appears to be selective for cells defective in p53 and therefore provides a potential, tumor-targeted therapy. Unfortunately, UCN-01 binds avidly to human plasma proteins, limiting access to the tumor. A screen of related indolocarbazoles identified analogues with both beneficial and undesirable properties. This led to a synthetic program to develop a novel analogue rationally designed to overcome the obstacles observed with the other analogues. We report the synthesis and analysis of a novel analogue, ICP-1. This analogue abrogated S and G2 phase arrest and enhanced cytotoxicity induced by cisplatin only in p53 defective cells. ICP-1 also abrogated arrest and enhanced cell killing induced by the topoisomerase I inhibitor SN38. Analysis of proteins that regulate cell cycle arrest suggest both drugs inhibit checkpoint kinases Chk1 and/or Chk2. In contrast to UCN-01, checkpoint abrogation by ICP-1 was only slightly inhibited by human plasma. UCN-01 and ICP-1 differed significantly in other regards. UCN-01 potently enhanced the activity of 1-beta-D-arabinofuranosylcytosine in both p53 wild-type and mutant cells, whereas ICP-1 was inactive in this combination. This property of UCN-01 was independent of its ability to inhibit protein kinase C because more specific inhibitors of protein kinase C failed to enhance cell killing induced by 1-beta-D-arabinofuranosylcytosine. High concentrations of UCN-01 also inhibit C-TAK1 that results in S phase-arrested cells directly entering mitosis, but this property was not observed with ICP-1. Hence, ICP-1 appears to be a more selective inhibitor of the S and G2 cell cycle checkpoint than previously studied analogues and is worthy of study in preclinical tumor models.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alkaloids / pharmacology*
  • Antineoplastic Agents / pharmacology*
  • Breast Neoplasms / drug therapy
  • Carbazoles*
  • Cell Cycle / drug effects*
  • Cell Division / drug effects
  • Cisplatin / pharmacology*
  • DNA / metabolism
  • DNA Damage / drug effects*
  • Dose-Response Relationship, Drug
  • Female
  • Flow Cytometry
  • G2 Phase / drug effects
  • Genes, p53
  • Humans
  • Immunoblotting
  • Indoles*
  • Models, Chemical
  • Mutation
  • Protein Binding
  • S Phase / drug effects
  • Staurosporine / analogs & derivatives*
  • Staurosporine / chemistry
  • Staurosporine / pharmacology*
  • Time Factors
  • Tumor Cells, Cultured


  • Alkaloids
  • Antineoplastic Agents
  • Carbazoles
  • ICP-1 compound
  • Indoles
  • 7-hydroxystaurosporine
  • DNA
  • Staurosporine
  • Cisplatin