Gli pathway-targeted Co(iii) Schiff base complexes inhibit migration of basal cell carcinoma cells

Abstract

Basal Cell Carcinoma (BCC) is the most frequently diagnosed cancer globally and affects about one in five Americans. Given the frequency of diagnosis, it is surprising that there are very few therapeutic options. Surgical removal is currently the most common treatment option; however, this can lead to noticeable scarring and cosmetic issues. As a result, there is a compelling interest in developing non-invasive therapeutic approaches to this disease. Here, we introduce a new transition metal-DNA derivative called CoGli-GOPEI that inhibits the migration of murine ASZ BCC cells in laboratory experiments. Notably, this complex significantly outperforms two established hedgehog-pathway inhibitors: GANT-61 (an investigational compound) and vismodegib (an FDA-approved drug). These inhibitors target the hedgehog signaling pathway-specifically the Gli family of transcription factors-to slow cancer progression. By effectively reducing cell migration, CoGli-GOPEI offers a less invasive alternative to traditional treatments like surgical resection and chemotherapy. Our results highlight how targeting the Gli transcription factors within the hedgehog pathway can create a novel therapeutic strategy against BCC. The ultimate goal of these new derivates is to reduce the spread of cancer cells while minimizing the downsides of surgery.

Fig. 1. Overview of the hedgehog signaling pathway in active (left) and inactive (right) states. The two compounds used for comparison are denoted next to the pathway component of inhibition (vismodegib and GANT-61)—the binding of hedgehog, Hh, ligands to PTCH1 results in the release of Gli transcription factors. The overactivation of this pathway underlies BCC oncogenesis and tumor growth.

Fig. 2. Structure and DNA sequence of CoGli. The Co(iii) Schiff base complex tethered to the Gli transcription factor targeted sequence. The asterisks denote phosphorothioate linkages on the 3′ and 5′ end to prevent degradation by endonucleases. The synthesis was done according to literature with modifications made to enhance yield.

Fig. 3. Normalized average percent migration for vismodegib and Gant-61. The two graphs display dosage for (A) vismodegib (purple) and (B) Gant-61 (blue), showing the normalized average percent area for a given dose. Standard errors of the normalized means were plotted, and a 2-tailed paired Student's t-test was used to determine statistical significance (p < 0.05). Each graph has two lines as to indicate the independent dosages tested during a single experiment.

Fig. 4. Normalized average percent migration for ASZ cells dosed with purified CoGli–GOPEI. (A) The chemical structure of CoGli–GOPEI that was used to dose the cells. (B) The normalized average percent area of migration is shown for each of the tested doses: 0 μM, 1 μM, 2.5 μM, 4 μM, and 8.5 μM. The separate lines indicate the doses tested on individual plates (black: 0 μM, 1 μM, 2.5 μM, and grey: 0 μM, 4 μM, 8.5 μM). (C and D) The standard error of the normalized means was plotted, and a 2-tailed paired Student's t-test was used to determine statistical significance (p < 0.05) between doses. In (C), p = 0.0074 (**), 0.00063 (***). In (D), p = 0.011 (*), 0.0075 (**).

Fig. 5. The effects of individual components of the CoGli–GOPEI compound on ASZ cell migration. (A) The chemical structure of [Co(acacen)(NH₃)₂]Cl is depicted and chosen as a representative cobalt(iii) Schiff base complex with the same equatorial ligand as the cobalt complex used in CoGli–GOPEI. (B) The structure of GOPEI is shown and used to assess the effects of this CoGli–GOPEI complex on cell inhibition. (C) The normalized average percent area migration of ASZ cells for a given dose of [Co(acacen)(NH₃)₂]Cl (blue). Acacen = bis(acetylacetone)ethylenediamine. (D) The normalized average percent area migration of ASZ cells for a given dose of GOPEI (orange). For (C and D), the standard error of the normalized means was plotted, and a 2-tailed paired Student's t-test was used to determine statistical significance (p < 0.05), p = 0.011.