The pyrrolopyrimidine colchicine-binding site agent PP-13 reduces the metastatic dissemination of invasive cancer cells in vitro and in vivo

Biochem Pharmacol. 2019 Feb;160:1-13. doi: 10.1016/j.bcp.2018.12.004. Epub 2018 Dec 7.

Abstract

Standard chemotherapies that interfere with microtubule dynamics are a chemotherapeutic option used for the patients with advanced malignancies that invariably relapse after targeted therapies. However, major efforts are needed to reduce their toxicity, optimize their efficacy, and reduce cancer chemoresistance to these agents. We previously identified a pyrrolo[2,3d]pyrimidine-based microtubule-depolymerizing agent (PP-13) that binds to the colchicine site of β-tubulin and exhibits anticancer properties in solid human cancer cells, including chemoresistant subtypes. Here, we investigated the therapeutic potential of PP-13 in vitro and in vivo. PP-13 induced a mitotic blockade and apoptosis in several cancer cells cultured in two-dimensions or three-dimensions spheroids, in conjunction with reduced cell proliferation. Capillary-like tube formation assays using HUVECs showed that PP-13 displayed antiangiogenic properties. It also inhibited cancer cell motility and invasion, in in vitro wound-healing and transwell migration assays. Low concentration PP-13 (130 nmol.L-1) treatment significantly reduced the metastatic invasiveness of human cancer cells engrafts on chicken chorioallantoic membrane. In nude mice, 0.5 or 1 mg.kg-1 PP-13 intraperitoneally administered three-times a week reduced the sizes of paclitaxel-refractory orthotopic breast tumors, delayed the progression of metastasis, and decreased the global metastatic load compared to 0.5 mg.kg-1 paclitaxel or vehicle alone. PP-13 did not show any apparent early adverse effect in vivo. These data suggest that PP-13 is a promising alternative to standard chemotherapy in antimitotic drug-refractory tumors, especially through its impact on metastasis.

Keywords: Drug-refractory tumors; Invasion; Metastasis; Paclitaxel; Pyrrolopyrimidine; Spheroids.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antimitotic Agents / chemistry
  • Antimitotic Agents / pharmacology
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / toxicity
  • Binding Sites
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Chick Embryo
  • Colchicine / metabolism*
  • Female
  • Humans
  • Mice, Inbred Strains
  • Neovascularization, Pathologic / drug therapy
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology*
  • Pyrimidines / toxicity
  • Pyrroles / chemistry
  • Pyrroles / pharmacology*
  • Pyrroles / toxicity
  • Spheroids, Cellular / drug effects
  • Spheroids, Cellular / pathology
  • Xenograft Model Antitumor Assays

Substances

  • Antimitotic Agents
  • Antineoplastic Agents
  • Pyrimidines
  • Pyrroles
  • Colchicine