Antimetastatic Properties of Prodigiosin and the BH3-Mimetic Obatoclax (GX15-070) in Melanoma

Abstract

Metastasis is the primary cause of death in cancer patients. Many current chemotherapeutic agents only show cytotoxic, but not antimetastatic properties. This leads to a reduction in tumor size, but allows cancer cells to disseminate, which ultimately causes patient death. Therefore, novel anticancer compounds with both effects need to be developed. In this work, we analyze the antimetastatic properties of prodigiosin and obatoclax (GX15-070), anticancer drugs of the Prodiginines (PGs) family. We studied PGs’ effects on cellular adhesion and morphology in the human primary and metastatic melanoma cell lines, SK-MEL-28 and SK-MEL-5, and in the murine melanoma cell line, B16F10A. Cell adhesion sharply decreased in the treated cells, and this was accompanied by a reduction in filopodia protrusions and a significant decrease in the number of focal-adhesion structures. Moreover, cell migration was assessed through the wound-healing assay and cell motility was severely inhibited after 24 h of treatment. To elucidate the molecular mechanisms involved, changes in metastasis-related genes were analyzed through a gene-expression array. Key genes related to cellular invasion, migration and chemoresistance were significantly down-regulated. Finally, an in vivo model of melanoma-induced lung metastasis was established and significant differences in lung tumors were observed in the obatoclax-treated mice. Altogether, these results describe, in depth, PGs’ cellular antimetastatic effects and identify in vivo antimetastatic properties of Obatoclax.

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“…PG has shown strong anti-cancer effects, with proven efficacy in treating melanoma, breast cancer, lung cancer, lymphocytic leukemia, and glioblastoma ( Pan et al, 2012 ; Brown et al, 2015 ; Wang et al, 2016 ; Cheng et al, 2018 ; Chiu et al, 2018 ; Espona-Fiedler et al, 2022 ). It triggers apoptosis in cancer cells, including multidrug-resistant ones, with minimal toxicity to normal cells ( Elahian et al, 2013 ).…”

“…Inhibiting tumor cell migration and motility is essential for achieving anti-cancer effects. Research by Margarita Espona-Fiedler and her team found that PGs effectively reduce the adhesive capability of melanoma cells, impeding their ability to colonize distant organs and preventing metastasis ( Espona-Fiedler et al, 2022 ). PG treatment also decreases the adhesive capacity of metastatic lung cancer cells and reduces filopodia formation in melanoma cells, which are crucial for cancer cell migration and proliferation.…”

New insights in application of mesenchymal stem cells therapy in tumor microenvironment: pros and cons

“…Surgical intervention and chemotherapy, as the most common therapeutic methods, may be associated with different complications ( Debela et al, 2021 ; Zeng et al, 2023 ). Despite the development of different therapy methods, metastatic tumors are mainly untreatable and are responsible for the preponderance of deaths due to cancer ( Espona-Fiedler et al, 2023 ). A major barrier to the development of efficient therapies is the complexity of tumors.…”