Author: Fragoso, Gladis ; Salas-Garrido, Carlos Gerardo ; Pérez-Osorio, Iván Nicolás ; Sifontes-Rodríguez, Sergio ; Rocha, Diego Moctezuma ; Hernández-Aceves, Juan Alberto ; Sciutto, Edda ; Villalobos, Nelly

Peptide drugs have emerged as an attractive alternative for cancer treatment due to their potency, high specificity, general safety and low cost. GK-1 is a linear 18 amino acid peptide with proven immunomodulator, antitumor and antimetastatic capacity in animal models. Preclinical toxicity studies for its use as a vaccine adjuvant demonstrated its safety in various assay systems, but a comprehensive exploration of its toxicity profile is required to be used in cancer immunotherapy. Therefore, in the present work, the potential toxicity of GK-1 was predicted with ToxinPred 3.0 software, and its in vitro cytotoxicity, and single-dose and repeated-dose toxicity by subcutaneous route in mice were experimentally assessed. GK-1 peptide was predicted as a non-toxic and did not exhibit in vitro cytotoxicity for several non-tumor and tumor cell lines and primary cell cultures at concentrations up to 500 µM, reinforcing previous studies pointing that the antitumoral effect of GK-1 was not mediated by tumor cell cytotoxicity. The single-dose toxicity study did not evidence local or systemic toxicity up to the maximum tested dose of 1000 mg/kg. Moreover, no toxic effects were observed in the repeated-dose toxicity study based on four doses administered weekly at up to 300 mg/kg. Considering that GK-1 is effective in triple-negative breast cancer and melanoma models in mice at doses as low as 5 mg/kg, the present results support the safety of GK-1 as an antitumoral peptide candidate.

17 Dec 2024·ACS Omega

Exploring the Mechanisms Underlying Cellular Uptake and Activation of Dendritic Cells by the GK-1 Peptide

Article

Author: Sciutto, Edda ; Vázquez Ramírez, Ricardo ; Alfonzo, Laura Bonifaz ; Cervantes-Torres, Jacquelynne ; Fragoso, Gladis ; Hernández-Aceves, Juan A. ; Gajón Martínez, Julián A. ; Mendoza Sierra, Luis ; Ramírez-Salinas, Gemma L. ; Moctezuma-Rocha, Diego ; Sifontes-Rodríguez, Sergio

The use of peptides for cancer immunotherapy is a promising and emerging approach that is being intensively explored worldwide. One such peptide, GK-1, has been shown to delay the growth of triple-negative breast tumors in mice, reduce their metastatic capacity, and reverse the intratumor immunosuppression that characterizes this model. Herein, it is demonstrated that GK-1 is taken up by bone marrow dendritic cells in a dose-dependent manner 15 min after exposure, more efficiently at 37 °C than at 4 °C, implying an entrance into the cells by energy-independent and -dependent processes through clathrin-mediated endocytosis. Theoretical predictions support the binding of GK-1 to the hydrophobic pocket of MD2, preventing it from bridging TLR4, thereby promoting receptor dimerization and cell activation. GK-1 can effectively activate cells via a TLR4-dependent pathway based on in vitro studies using HEK293 and HEK293-TLR4-MD2 cells and in vivo using C3H/HeJ mice (hyporesponsive to LPS). In conclusion, GK-1 enters the cells by passive diffusion and by activation of the transmembrane Toll-like receptor 4 triggering cell activation, which could be involved in the GK-1 antitumor properties.

01 Mar 2020·Clinical ImmunologyQ3 · MEDICINE

The helminth-derived peptide GK-1 induces an anti-tumoral CD8 T cell response associated with downregulation of the PD-1/PD-L1 pathway

Q3 · MEDICINE

Article

Author: Cervantes-Torres, Jacquelynne ; Sánchez-Miranda, Elizabeth ; Rodríguez-Rodríguez, Noé ; Madera-Salcedo, Iris K ; Torres-García, Diana ; Rosetti, Florencia ; Crispín, José C ; Fragoso, Gladis ; Sciutto, Edda ; Bugarin-Estrada, Emmanuel

CD8 T cells can kill malignant cells in an antigen-specific manner. However, anti-tumoral responses are usually limited by suppressive factors that curb the effector responses of tumor-infiltrating CD8 T cells. Therapeutic strategies to overcome intra-tumoral T cell suppression, for example immune checkpoint inhibition, have been clinically effective in patients with cancer. Here, we provide data that demonstrates that GK-1, a peptide derived from the parasite Taenia crassiceps, promotes an anti-melanoma CD8 T cell response with heightened effector characteristics that leads to an increased amount of tumor-infiltrating CD44⁺ IFN-γ-producing CD8 T cells. The response induced by GK-1 was associated with a reduction in the expression of PD-1 and PD-L1 on tumor-infiltrating CD8 and dendritic cells, respectively, effects that led to a dramatic decrease in tumor burden. Our results suggest that the immunomodulatory properties of GK-1 may promote a CD8 T cell response that may be therapeutically useful in the setting of cancer.

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