Simultaneous Activation of Immunogenic Cell Death and cGAS-STING Pathway by Liver- and Mitochondria-Targeted Gold(I) Complexes for Chemoimmunotherapy of Hepatocellular Carcinoma.

Induction of immunogenic cell death (ICD) and activation of the cyclic GMP-AMP synthase stimulator of interferon gene (cGAS-STING) pathway are two potent anticancer immunotherapeutic strategies in hepatocellular carcinoma (HCC). Herein, 12 liver- and mitochondria-targeting gold(I) complexes (9a-9l) were designed and synthesized. The superior complex 9b produced a considerable amount of reactive oxygen species (ROS) and facilitated DNA excretion, the ROS-induced ICD and DNA activated the cGAS-STING pathway, both of which evoked an intense anticancer immune response in vitro and in vivo. Importantly, 9b strongly inhibited tumor growth in a patient-derived xenograft model of HCC. Overall, we present the first case of simultaneous ICD induction and cGAS-STING pathway activation within the same gold-based small molecule, which may provide an innovative strategy for designing chemoimmunotherapies for HCC.

Design, synthesis and biological evaluation of fluorinated selective estrogen receptor degraders (FSERDs) --- A promising strategy for advanced ER positive breast cancer.

Although endocrine therapies involving pharmaceuticals, such as tamoxifen and aromatase inhibitors, had initially demonstrated good responses in patients with estrogen receptor-positive (ER+) breast cancer, they often led to drug resistance. ER plays a vital role in the progression of metastatic diseases. Fulvestrant, a first generation selective estrogen receptor degrader (SERD), can effectively downregulate the ER protein and inhibit its downstream signaling pathways. However, as the drug needs to be intramuscularly injected, its widespread use is limited owing to poor patient compliance. Herein, we described a novel class of orally bioavailable fluorine-substituted SERDs that exhibit improved pharmacokinetic profiles. We substituted the hydroxyl group of clinical SERD candidate 6 with a fluorine atom to diminish phase II metabolism. The subsequent structure-activity relationship (SAR) investigation identified 22h and 27b, which can effectively degrade ER in a dose-dependent manner and exhibit considerable antiproliferative potency and efficacy in vitro and in vivo. The excellent pharmacokinetic profiles of 27b render it promising candidate of clinically useful oral SERD.

SERD-NHC-Au(I) complexes for dual targeting ER and TrxR to induce ICD in breast cancer.

The development of selective estrogen receptor degraders (SERDs) has brought new ideas for the clinical treatment of ER-positive advanced breast cancer. The successful application of combinational therapy inspired the exploration of other targets to prevent breast cancer progression. Thioredoxin reductase (TrxR) is an important enzyme that can regulate redox balance in cells and it was considered as a potential target for anticancer treatment. In this study, we firstly combine a clinical SERD candidate--G1T48 (NCT03455270), with a TrxR inhibitor--N-heterocyclic carbene gold(I) [NHC-Au(I)] to form dual targeting complexes that can regulate both signaling pathways. The most efficacious complex 23 exhibited significant antiproliferative profile through degrading ER and inhibiting TrxR activity. Interestingly, it can induce immunogenic cell death (ICD) caused by ROS. This is the first evidence to elucidate the role of ER/TrxR-ROS-ICD axis in ER positive breast cancer and this research may inspire new drug development with novel mechanisms. The in vivo xenograft study demonstrated that complex 23 had excellent antiproliferative activity toward MCF-7 cells in mice model.

Tumor-Targeting NHC-Au(I) Complex Induces Immunogenic Cell Death in Hepatocellular Carcinoma.

Immunogenic cell death (ICD) is a promising direction of cancer immunotherapy in hepatocellular carcinoma (HCC). A series of novel NHC-Au(I) complexes derived from 4,5-diarylimidazole, containing glycyrrhetinic acid (GA) as an efficient targeting ligand for HCC, were herein designed and synthesized. Among these, complex 4C exhibited excellent effectiveness for tumor targeting and antitumor activity, which induced the occurrence of ICD in HCC cells. Additionally, 4C can effectively inhibit TrxR enzyme activity, increase reactive oxygen species (ROS) expression, lead to redox homeostasis disorder, mediate mitochondrial dysfunction and endoplasmic reticulum stress (ERS), and cause the characteristic discharge of damage-associated molecular patterns (DAMPs) in HCC cells. More importantly, 4C showed a great ICD-inducing effect in a vaccination mouse model and activated antitumor immunity in a tumor-bearing C57BL/6 mouse model, which is consistent with the in vitro results. In conclusion, we found the potential of Au(I) complex with HCC-targeted capability for effective tumor immunotherapy.

Recent development of gold(I) and gold(III) complexes as therapeutic agents for cancer diseases.

Metal complexes have demonstrated significant antitumor activities and platinum complexes are well established in the clinical application of cancer chemotherapy. However, the platinum-based treatment of different types of cancers is massively hampered by severe side effects and resistance development. Consequently, the development of novel metal-based drugs with different mechanism of action and pharmaceutical profile attracts modern medicinal chemists to design and synthesize novel metal-based agents. Among non-platinum anticancer drugs, gold complexes have gained considerable attention due to their significant antiproliferative potency and efficacy. In most situations, the gold complexes exhibit anticancer activities by targeting thioredoxin reductase (TrxR) or other thiol-rich proteins and enzymes and trigger cell death via reactive oxygen species (ROS). Interestingly, gold complexes were recently reported to elicit biochemical hallmarks of immunogenic cell death (ICD) as an ICD inducer. In this review, the recent progress of gold(I) and gold(III) complexes is comprehensively summarized, and their activities and mechanism of action are documented.

ApoE deficiency promotes non-alcoholic fatty liver disease in mice via impeding AMPK/mTOR mediated autophagy.

AIM: This work was to investigate the relationship between ApoE and autophagy regulated by AMPK/mTOR pathway in the pathological process of NAFLD. MAIN METHODS: Both WT and ApoE-/- mice were divided into two groups and allocated into either a normal chow (ND) or a high-fat diet (HFD) for 8 weeks. After that, we detected the indicators of lipid accumulation, hepatic injury, mitochondrial function hallmark, autophagy, apoptosis, inflammation, and oxidative stress by commercially available kits, immunohistochemistry, immunofluorescent staining, and western blot. KEY FINDING: We found the lipid levels of serum and liver, and hepatic injury were significantly increased in the ApoE-/--HFD group compared to other groups. ApoE-/- mice exhibited increased deposition of fat in liver tissue. The PGC1α, NRF1, ATP, p-AMPK, AMPK, Beclin1, and LC3 levels were downregulated and ROS, p-mTOR, and mTOR were increased in the ApoE-/--HFD group compared to WT-HFD group. When treated with AMPK and autophagy activators, AICAR and rapamycin, these pathologies and protein levels can be rescued. The expression levels of apoptosis-related proteins, inflammation, and oxidative stress were increased in the ApoE-/--HFD group compared to the WT-HFD group. SIGNIFICANCE: Our results indicated that ApoE deficiency can regulate AMPK/mTOR pathway, which leads to NAFLD most likely by modulating hepatic mitochondrial function.