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

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.

Auranofin and its analogs as prospective agents for the treatment of colorectal cancer

Today colorectal cancer (CRC) is one of the leading causes of cancer death worldwide. This disease is poorly chemo-sensitive toward the existing medical treatments so that new and more effective therapeutic agents are urgently needed and intensely sought. Platinum drugs, oxaliplatin in particular, were reported to produce some significant benefit in CRC treatment, triggering the general interest of medicinal chemists and oncologists for metal-based compounds as candidate anti-CRC drugs. Within this frame, gold compounds and, specifically, the established antiarthritic drug auranofin with its analogs, form a novel group of promising anticancer agents. Owing to its innovative mechanism of action and its favorable pharmacological profile, auranofin together with its derivatives are proposed here as novel experimental agents for CRC treatment, capable of overcoming resistance to platinum drugs. Some encouraging results in this direction have already been obtained. A few recent studies demonstrate that the action of auranofin may be further potentiated through the preparation of suitable pharmaceutical formulations capable of protecting the gold pharmacophore from unselective reactivity or through the design of highly synergic drug combinations. The perspectives of the research in this field are outlined.

Gold Compounds Inhibit the Ca2+-ATPase Activity of Brain PMCA and Human Neuroblastoma SH-SY5Y Cells and Decrease Cell Viability

Plasma membrane calcium ATPases (PMCA) are key proteins in the maintenance of calcium (Ca2+) homeostasis. Dysregulation of PMCA function is associated with several human pathologies, including neurodegenerative diseases, and, therefore, these proteins are potential drug targets to counteract those diseases. Gold compounds, namely of Au(I), are well-known for their therapeutic use in rheumatoid arthritis and other diseases for centuries. Herein, we report the ability of dichloro(2-pyridinecarboxylate)gold(III) (1), chlorotrimethylphosphinegold(I) (2), 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidenegold(I) chloride (3), and chlorotriphenylphosphinegold(I) (4) compounds to interfere with the Ca2+-ATPase activity of pig brain purified PMCA and with membranes from SH-SY5Y neuroblastoma cell cultures. The Au(III) compound (1) inhibits PMCA activity with the IC50 value of 4.9 µM, while Au(I) compounds (2, 3, and 4) inhibit the protein activity with IC50 values of 2.8, 21, and 0.9 µM, respectively. Regarding the native substrate MgATP, gold compounds 1 and 4 showed a non-competitive type of inhibition, whereas compounds 2 and 3 showed a mixed type of inhibition. All gold complexes showed cytotoxic effects on human neuroblastoma SH-SY5Y cells, although compounds 1 and 3 were more cytotoxic than compounds 2 and 4. In summary, this work shows that both Au (I and III) compounds are high-affinity inhibitors of the Ca2+-ATPase activity in purified PMCA fractions and in membranes from SH-SY5Y human neuroblastoma cells. Additionally, they exert strong cytotoxic effects.

Gold Compounds and the Anticancer Immune Response

Gold compounds are not only well-explored for cytotoxic effects on tumors, but are also known to interact with the cancer immune system. The immune system deploys innate and adaptive mechanisms to protect against pathogens and prevent malignant transformation. The combined action of gold compounds with the activated immune system has shown promising results in cancer therapy through in vivo and in vitro experiments. Gold compounds are known to induce innate immune responses; however, these responses may contribute to adaptive immune responses. Gold compounds play the role of a major hapten that acts synergistically in innate immunity. Gold compounds support cancer cell antigenicity and promote anti-tumor immune response by inducing the release of CRT, ATP, HMGB1, HSP, and NKG2D to enhance immunogenicity. Gold compounds affect various immune cells (including suppressor regulatory T cells), inhibit myeloid derived suppressor cells, and enhance the function and number of dendritic cells. Gold nanoparticles (AuNPs) have potential for improving the effect of immunotherapy and reducing the toxicity and side effects of the treatment process. Thus, AuNPs provide an ideal opportunity for exploring the combination of anticancer gold compounds and immunotherapeutic interventions.

Current Progress and Perspectives on Using Gold Compounds for the Modulation of Tumor Cell Metabolism

Altered cellular metabolism, which is essential for the growth and survival of tumor cells in a specific microenvironment, is one of the hallmarks of cancer. Among the most significant changes in the metabolic pattern of tumor cells is the shift from oxidative phosphorylation to aerobic glycolysis for glucose utilization. Tumor cells also exhibit changes in patterns of protein and nucleic acid metabolism. Recently, gold compounds have been shown to target several metabolic pathways and a number of metabolites in tumor cells. In this review, we summarize how gold compounds modulate glucose, protein, and nucleic acid metabolism in tumor cells, resulting in anti-tumor effects. We also discuss the rationale underlying the anti-tumor effects of these gold compounds and highlight how to effectively utilize against various types of tumors.

Auranofin-Mediated NRF2 Induction Attenuates Interleukin 1 Beta Expression in Alveolar Macrophages

Background: Alveolar macrophages (AMs) are resident inflammatory cells in the lung that serve as early sentinels of infection or injury. We have identified thioredoxin reductase 1 inhibition by gold compounds increases activation of nuclear factor erythroid 2-related factor 2 (NRF2)-dependent pathways to attenuate inflammatory responses. The present studies utilized murine alveolar macrophages (MH-S) to test the hypothesis that the gold compound, auranofin (AFN), decreases interleukin (IL)-1β expression through NRF2-mediated interactions with nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway genes and/or increases in glutathione synthesis. Methods: MH-S cells were treated with AFN and lipopolysaccharide (LPS) and analyzed at 6 and 24 h. The Il1b promoter was analyzed by chromatin immunoprecipitation for direct interaction with NRF2. Results: Expression of IL-1β, p-IκBα, p-p65 NF-kB, and NOD-, LRR-, and pyrin domain-containing protein 3 were elevated by LPS exposure, but only IL-1β expression was suppressed by AFN treatment. Both AFN and LPS treatments increased cellular glutathione levels, but attenuation of glutathione synthesis by buthionine sulfoximine (BSO) did not alter expression of Il-1β. Analysis revealed direct NRF2 binding to the Il1b promoter which was enhanced by AFN and inhibited the transcriptional activity of DNA polymerase II. Conclusions: Our data demonstrate that AFN-induced NRF2 activation directly suppresses IL-1β synthesis independent of NFκB and glutathione-mediated antioxidant mechanisms. NRF2 binding to the promoter region of IL1β directly inhibits transcription of the IL1β gene. Collectively, our research suggests that gold compounds elicit NRF2-dependent pulmonary protection by suppressing macrophage-mediated inflammation.

Multi-Targeted Anticancer Activity of Imidazolate Phosphane Gold(I) Compounds by Inhibition of DHFR and TrxR in Breast Cancer Cells

A class of phosphane gold(I) compounds, made of azoles and phosphane ligands, was evaluated for a screening on the regards of Breast Cancer cell panels (BC). The compounds possess N-Au-P or Cl-Au-P bonds around the central metal, and they differ for the presence of aprotic or protic polar groups in the azoles and/or the phosphane moieties to tune their hydrophilicity. Among the six candidates, only the compounds having the P-Au-N environment and not displaying neither the hydroxyl nor carboxyl groups in the ligands were found active. The compounds were screened by MTT tests in SKBR3, A17, and MDA-MB231 cancer cells, and two compounds (namely the 4,5-dicyano-imidazolate-1yl-gold(I)-(triphenylphosphane, 5, and 4,5-dichloro-imidazolate-1yl-gold(I)-triphenylphosphane, 6) were found very cytotoxic, with the most active with an IC50 value of 3.46 μM in MDA-MB231 cells. By performing enzymatic assays in the treated cells lysates, the residual enzymatic activity of dihydrofolate reductase (DHFR) has been measured after cell treatment for 4 or 12 h in comparison with control cells. Upon 12 h of treatment, the activity of DHFR was significantly reduced in both SKBR3 and A17 cells by compounds 5 and 6, but not in human MDA-MB231 cells; interestingly, it was found remarkably high after 4 h of treatment, revealing a time dependence for the DHFR enzymatic assays. The DHFR inhibition data have been compared to those for the thioredoxin reductase (TrxR), the most recognized molecular target for gold compounds. For this latter, similar residual activities (i.e., 37 and 49% for the match of SKBR3 cells and compound 5 or 6, respectively) were found. Binding studies on the regards of ct-DNA (calf-thymus-DNA) and of plasma transporters proteins, such as BSA (bovine serum albumin) and ATF (apo transferrin), were performed. As expected for gold compounds, the data support strong binding to proteins (Ksv values range: 1.51 ÷ 2.46 × 104 M−1) and a weaker interaction with ct-DNA's minor groove (Ksv values range: 1.55 ÷ 6.12 × 103 M−1).

Medicinal Au(i) compounds targeting urease as prospective antimicrobial agents: unveiling the structural basis for enzyme inhibition

A few gold compounds were recently found to show antimicrobial properties in vitro, holding great promise for the discovery of new drugs to overcome antibiotic resistance.