Breast Cancer Treatment: The Case of Gold(I)-Based Compounds as a Promising Class of Bioactive Molecules

Abstract

Breast cancers (BCs) may present dramatic diagnoses, both for ineffective therapies and for the limited outcomes in terms of lifespan. For these types of tumors, the search for new drugs is a primary necessity. It is widely recognized that gold compounds are highly active and extremely potent as anticancer agents against many cancer cell lines. The presence of the metal plays an essential role in the activation of the cytotoxicity of these coordination compounds, whose activity, if restricted to the ligands alone, would be non-existent. On the other hand, gold exhibits a complex biochemistry, substantially variable depending on the chemical environments around the central metal. In this review, the scientific findings of the last 6–7 years on two classes of gold(I) compounds, containing phosphane or carbene ligands, are reviewed. In addition to this class of Au(I) compounds, the recent developments in the application of Auranofin in regards to BCs are reported. Auranofin is a triethylphosphine-thiosugar compound that, being a drug approved by the FDA—therefore extensively studied—is an interesting lead gold compound and a good comparison to understand the activities of structurally related Au(I) compounds.

Shifting the Antibody–Drug Conjugate Paradigm: A Trastuzumab-Gold-Based Conjugate Demonstrates High Efficacy against Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer Mouse Model

“…In the Supporting Information (Table S4), we include tables with IC 50 values of gold precursors that could not be bioconjugated as well as IC 50 values in lung IMR90 fibroblasts (Table S5). We found that precursors ( 2a and 5a ) and NHS payloads ( 2c and 5c ) exhibited cytotoxicity against all cell lines in the low micromolar range (Table ), with some sensitivity toward MDA-MB-231, which can be explained by the high toxicity displayed by several gold­(I) phosphane-containing compounds against triple-negative breast cancers. – After conjugation to trastuzumab and pertuzumab, both sets of ADCs ( Tras-2c , Per-2c , Tras-5c , and Per-5c ) exhibited higher cytotoxicity against cells overexpressing HER2 (BT-474 and SKBR-3) with IC 50 values in the submicromolar range. More significantly, for SKBR-3 cells, the IC 50 values for 2c and Tras-2c show a 10-fold increase in toxicity for the ADC.…”

Development of immunoliposomes containing cytotoxic gold payloads against HER2-positive breast cancers

“…The IC 50 values of 3 against the different HER2+ and HER2− cancer cell lines and IMR-90 were observed to be high (>60 μM), as previously reported for other cancer cell lines. 50 Encapsulating 3 into liposomes and immunoliposomes did not significantly affect viability. High IC 50 values of 54.7 ± 7.3 μM for Lipo- 3 and 52.6 ± 5.4 μM for Opt-Immunolipo-Tras- 3 were obtained.…”

“…This is expected, as the IC 50 of trastuzumab against all cell lines easily exceeds 50 μM. 23,50 Optimization of trastuzumab-based immunoliposome size for specific gold compounds With the previous experiments described, we have shown the facile preparation of gold-containing liposomes and demonstrated that engrafting specific mAbs onto these vehicles can induce targeting selectivity and toxicity toward cells overexpressing an antigen recognized by these mAbs. We showed these gold-containing lipo-and immunoliposomes to be <200 nm in diameter, a precondition for the EPR effect that allows nanoparticles to accumulate in tumor environments.…”

Design, Synthesis, and Preclinical Activity in Ovarian Cancer Models of New Phosphanegold(I)-N-heterocyclic Carbene Complexes

“…To improve gold­(I) compound pharmacokinetics, transport through the cell, tumor selectivity, lipophilicity, ,, and antitumoral activity against cisplatin resistant cancer cells, , we incorporated chiral phosphine ligands (L2–L5) or tricyclohexylphosphine (L6) into our metal-based drug candidates. Indeed, tricyclohexylphosphine (L6), widely used in biological systems, has been shown to exhibit the highest activity against cisplatin-resistant DU145 human prostate cancer cells among the studied complexes. , …”