CIGB-300, a novel proapoptotic peptide that impairs the CK2 phosphorylation and exhibits anticancer properties both in vitro and in vivo.
Protein Kinase CK2 is a serine-threonine kinase frequently deregulated in many human tumors. Here, we hypothesized that a peptide binder to the CK2 phosphoacceptor site could exhibit anticancer properties in vitro, in tumor animal models, and in cancer patients. By screening a random cyclic peptide phage display library, we identified the CIGB-300 (formerly P15-Tat), a cyclic peptide which abrogates the CK2 phosphorylation by blocking recombinant substrates in vitro. Interestingly, synthetic CIGB-300 led to a dose-dependent antiproliferative effect in a variety of tumor cell lines and induced apoptosis as evidenced by rapid caspase activation. Importantly, CIGB-300 elicited significant antitumor effect both by local and systemic administration in murine syngenic tumors and human tumors xenografted in nude mice. Finally, we performed a First-in-Man trial with CIGB 300 in patients with cervical malignancies. The peptide was found to be safe and well tolerated in the dose range studied. Likewise, signs of clinical benefit were clearly identified after the CIGB-300 treatment as evidenced by significant decrease of the tumor lesion area and histological examination. Our results provide an early proof-of-principle of clinical benefit by using an anti-CK2 approach in cancer. Furthermore, this is the first clinical trial where an investigational drug has been used to target the CK2 phosphorylation domain.
Perea
Silvio E
SE
Center for Genetic Engineering and Biotechnology (CIGB), Havana, 10600, Cuba. silvio.perea@cigb.edu.cu
Reyes
Osvaldo
O
Baladron
Idania
I
Perera
Yasser
Y
Farina
Hernán
H
Gil
Jeovanis
J
Rodriguez
Arielis
A
Bacardi
Dania
D
Marcelo
Jose L
JL
Cosme
Karelia
K
Cruz
Marisol
M
Valenzuela
Carmen
C
López-Saura
Pedro A
PA
Puchades
Yaquelin
Y
Serrano
Joem M
JM
Mendoza
Osmani
O
Castellanos
Lila
L
Sanchez
Aniel
A
Betancourt
Lazaro
L
Besada
Vladimir
V
Silva
Ricardo
R
López
Ernesto
E
Falcón
Viviana
V
Hernández
Ignacio
I
Solares
Margarita
M
Santana
Agueda
A
Díaz
Alina
A
Ramos
Thelvia
T
López
Carlos
C
Ariosa
Juan
J
González
Luis J
LJ
Garay
Hilda
H
Gómez
Daniel
D
Gómez
Roberto
R
Alonso
Daniel F
DF
Sigman
Hugo
H
Herrera
Luis
L
Acevedo
Boris
B
D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001681:Biological Assay; D047390:Casein Kinase II / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009856:Oncogene Proteins, Viral / Q000378:metabolism; D050725:Papillomavirus E7 Proteins; D010456:Peptides, Cyclic / Q000009:adverse effects / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D020543:Proteome / Q000032:analysis; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D010456:Peptides, Cyclic; D020543:Proteome; C059731:oncogene protein E7, Human papillomavirus type 16; D047390:Casein Kinase II; C532510:CIGB-300