The Rac Inhibitor EHop-016 Inhibits Mammary Tumor Growth and Metastasis in a Nude Mouse Model.
Metastatic disease still lacks effective treatments, and remains the primary cause of cancer mortality. Therefore, there is a critical need to develop better strategies to inhibit metastatic cancer. The Rho family GTPase Rac is an ideal target for anti-metastatic cancer therapy, because Rac is a key molecular switch that is activated by a myriad of cell surface receptors to promote cancer cell migration/invasion and survival. Previously, we reported the design and development of EHop-016, a small molecule compound, which inhibits Rac activity of metastatic cancer cells with an IC50 of 1 μM. EHop-016 also inhibits the activity of the Rac downstream effector p21-activated kinase (PAK), lamellipodia extension, and cell migration in metastatic cancer cells. Herein, we tested the efficacy of EHop-016 in a nude mouse model of experimental metastasis, where EHop-016 administration at 25 mg/kg body weight (BW) significantly reduced mammary fat pad tumor growth, metastasis, and angiogenesis. As quantified by UPLC MS/MS, EHop-016 was detectable in the plasma of nude mice at 17 to 23 ng/ml levels at 12 h following intraperitoneal (i.p.) administration of 10 to 25 mg/kg BW EHop-016. The EHop-016 mediated inhibition of angiogenesis In Vivo was confirmed by immunohistochemistry of excised tumors and by In Vitro tube formation assays of endothelial cells. Moreover, EHop-016 affected cell viability by down-regulating Akt and Jun kinase activities and c-Myc and Cyclin D expression, as well as increasing caspase 3/7 activities in metastatic cancer cells. In conclusion, EHop-016 has potential as an anticancer compound to block cancer progression via multiple Rac-directed mechanisms.
Department of Biochemistry, School of Medicine, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico ; Department of Pathology and Laboratory Medicine, Universidad Central del Caribe, School of Medicine, Bayamón, Puerto Rico.
Linette
L
Castillo-Pichardo
Department of Biochemistry, School of Medicine, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico.
Tessa
T
Humphries-Bickley
Department of Biochemistry, School of Medicine, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico.
Columba
C
De La Parra
Department of Pharmaceutical Sciences, School of Pharmacy, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico.
Ingrid
I
Forestier-Roman
Department of Pharmaceutical Sciences, School of Pharmacy, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico.
Magaly
M
Martinez-Ferrer
Department of Pharmaceutical Sciences, School of Pharmacy, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico.
Eliud
E
Hernandez
Department of Pharmaceutical Sciences, School of Pharmacy, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico.
Cornelis
C
Vlaar
Department of Biology, University of Puerto Rico, Rio Piedras, Puerto Rico.
Yancy
Y
Ferrer-Acosta
Department of Biology, University of Puerto Rico, Rio Piedras, Puerto Rico.
Anthony V
AV
Washington
Department of Anatomy and Cell Biology, Universidad Central del Caribe, School of Medicine, Bayamón, Puerto Rico.
Luis A
LA
Cubano
Department of Biochemistry, School of Medicine, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico.
Jose
J
Rodriguez-Orengo
Department of Biochemistry, School of Medicine, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico.
Suranganie
S
Dharmawardhane