Characterization of a Dual Rac/Cdc42 Inhibitor MBQ-167 in Metastatic Cancer.

Abstract

The Rho GTPases Rac (Ras-related C3 botulinum toxin substrate) and Cdc42 (cell division control protein 42 homolog) regulate cell functions governing cancer malignancy, including cell polarity, migration, and cell-cycle progression. Accordingly, our recently developed Rac inhibitor EHop-016 (IC50, 1,100 nmol/L) inhibits cancer cell migration and viability and reduces tumor growth, metastasis, and angiogenesis in vivo Herein, we describe MBQ-167, which inhibits Rac and Cdc42 with IC50 values of 103 and 78 nmol/L, respectively, in metastatic breast cancer cells. Consequently, MBQ-167 significantly decreases Rac and Cdc42 downstream effector p21-activated kinase (PAK) signaling and the activity of STAT3, without affecting Rho, MAPK, or Akt activities. MBQ-167 also inhibits breast cancer cell migration, viability, and mammosphere formation. Moreover, MBQ-167 affects cancer cells that have undergone epithelial-to-mesenchymal transition by a loss of cell polarity and inhibition of cell surface actin-based extensions to ultimately result in detachment from the substratum. Prolonged incubation (120 hours) in MBQ-167 decreases metastatic cancer cell viability with a GI50 of approximately 130 nmol/L, without affecting noncancer mammary epithelial cells. The loss in cancer cell viability is due to MBQ-167-mediated G2-M cell-cycle arrest and subsequent apoptosis, especially of the detached cells. In vivo, MBQ-167 inhibits mammary tumor growth and metastasis in immunocompromised mice by approximately 90%. In conclusion, MBQ-167 is 10× more potent than other currently available Rac/Cdc42 inhibitors and has the potential to be developed as an anticancer drug, as well as a dual inhibitory probe for the study of Rac and Cdc42. Mol Cancer Ther; 16(5); 805-18. ©2017 AACR.

• Authors: Tessa Humphries-Bickley, Linette Castillo-Pichardo, Eliud Hernandez-O'Farrill, Luis D Borrero-Garcia, Ingrid Forestier-Roman, Yamil Gerena, Manuel Blanco, Michael J Rivera-Robles, José R Rodriguez-Medina, Luis A Cubano, Cornelis P Vlaar, Suranganie Dharmawardhane
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 16 Issue 5 Pg. 805-818 (05 2017) ISSN: 1538-8514 [Electronic] United States
• PMID: 28450422 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: ©2017 American Association for Cancer Research.

Chemical References

• Antineoplastic Agents
• Carbazoles
• N4-(9-ethyl-9H-carbazol-3-yl)-N2-(3-morpholin-4-ylpropyl)-pyrimidine-2,4-diamine
• Pyrimidines
• cdc42 GTP-Binding Protein
• rac1 GTP-Binding Protein

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Breast Neoplasms (drug therapy, genetics, pathology)
• Carbazoles (administration & dosage)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Female
• Humans
• Mice
• Neoplasm Metastasis
• Neovascularization, Pathologic (drug therapy, genetics, pathology)
• Pyrimidines (administration & dosage)
• Signal Transduction (drug effects)
• cdc42 GTP-Binding Protein (antagonists & inhibitors, genetics)
• rac1 GTP-Binding Protein (antagonists & inhibitors, genetics)