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.
Center for Genetic Engineering and Biotechnology (CIGB), Havana, 10600, Cuba. silvio.perea@cigb.edu.cu
Silvio E
SE
Perea
Osvaldo
O
Reyes
Idania
I
Baladron
Yasser
Y
Perera
Hernán
H
Farina
Jeovanis
J
Gil
Arielis
A
Rodriguez
Dania
D
Bacardi
Jose L
JL
Marcelo
Karelia
K
Cosme
Marisol
M
Cruz
Carmen
C
Valenzuela
Pedro A
PA
López-Saura
Yaquelin
Y
Puchades
Joem M
JM
Serrano
Osmani
O
Mendoza
Lila
L
Castellanos
Aniel
A
Sanchez
Lazaro
L
Betancourt
Vladimir
V
Besada
Ricardo
R
Silva
Ernesto
E
López
Viviana
V
Falcón
Ignacio
I
Hernández
Margarita
M
Solares
Agueda
A
Santana
Alina
A
Díaz
Thelvia
T
Ramos
Carlos
C
López
Juan
J
Ariosa
Luis J
LJ
González
Hilda
H
Garay
Daniel
D
Gómez
Roberto
R
Gómez
Daniel F
DF
Alonso
Hugo
H
Sigman
Luis
L
Herrera
Boris
B
Acevedo
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