Tumor-Infiltrating iNKT Cells Activated through c-Kit/Sca-1 Are Induced by Pentoxifylline, Norcantharidin, and Their Mixtures for Killing Murine Melanoma Cells.

The involvement of NK and other cytotoxic cells is considered the first defense line against cancer. However, a significant lack of information prevails on the possible roles played by factors considered characteristic of primitive cells, such as c-kit and Sca-1, in activating these cells, particularly in melanoma models subjected to treatments with substances under investigation, such as the case of norcantharidin. In this study, B16F1 murine melanoma cells were used to induce tumors in DBA/2 mice, estimating the proportions of NK and iNKT cells; the presence of activation (CD107a+) and primitive/activation (c-kit+/Lya6A+) markers and some tumor parameters, such as the presence of mitotic bodies, nuclear factor area, NK and iNKT cell infiltration in the tumor, infiltrated tumor area, and infiltrating lymphocyte count at 10x and 40x in specimens treated with pentoxifylline, norcantharidin, and the combination of both drugs. Possible correlations were estimated with Pearson's correlation analysis. It should be noted that, despite having demonstrated multiple correlations, immaturity/activation markers were related to these cells' activation. At the tumor site, iNKT cells are the ones that exert the cytotoxic potential on tumor cells, but they are confined to specific sites in the tumor. Due to the higher number of interactions of natural killer cells with tumor cells, it is concluded that the most effective treatment was PTX at 60 mg/kg + NCTD at 0.75 mg/kg.

Effectiveness of radiotherapy and targeted radionuclide therapy for melanoma in preclinical mouse models: A combination treatments overview.

Cutaneous melanoma is an aggressive and highly metastatic skin cancer. In recent years, immunotherapy and targeted small-molecule inhibitors have improved the overall survival of patients. Unfortunately, most patients in advanced stages of disease exhibit either intrinsically resistant or rapidly acquire resistance to these approved treatments. However, combination treatments have emerged to overcome resistance, and novel treatments based on radiotherapy (RT) and targeted radionuclide therapy (TRT) have been developed to treat melanoma in the preclinical mouse model, raising the question of whether synergy in combination therapies may motivate and increase their use as primary treatments for melanoma. To help clarify this question, we reviewed the studies in preclinical mouse models where they evaluated RT and TRT in combination with other approved and unapproved therapies from 2016 onwards, focusing on the type of melanoma model used (primary tumor and or metastatic model). PubMed® was the database in which the search was performed using mesh search algorithms resulting in 41 studies that comply with the inclusion rules of screening. Studies reviewed showed that synergy with RT or TRT had strong antitumor effects, such as tumor growth inhibition and fewer metastases, also exhibiting systemic protection. In addition, most studies were carried out on antitumor response for the implanted primary tumor, demonstrating that more studies are needed to evaluate these combined treatments in metastatic models on long-term protocols.