Regulating tumor glycometabolism and the immune microenvironment by inhibiting lactate dehydrogenase with platinum(iv) complexes.

Lactate dehydrogenase (LDH) is a key enzyme involved in the process of glycolysis, assisting cancer cells to take in glucose and generate lactate, as well as to suppress and evade the immune system by altering the tumor microenvironment (TME). Platinum(iv) complexes MDP and DDP were prepared by modifying cisplatin with diclofenac at the axial position(s). These complexes exhibited potent antiproliferative activity against a panel of human cancer cell lines. In particular, DDP downregulated the expression of LDHA, LDHB, and MCTs to inhibit the production and influx/efflux of lactate in cancer cells, impeding both glycolysis and glucose oxidation. MDP and DDP also reduced the expression of HIF-1α, ARG1 and VEGF, thereby disrupting the formation of tumor vasculature. Furthermore, they promoted the repolarization of macrophages from the tumor-supportive M2 phenotype to the tumor-suppressive M1 phenotype in the TME, thus enhancing the antitumor immune response. The antitumor mechanism involves reprogramming the energy metabolism of tumor cells and relieving the immunosuppressive TME.

Immunogenicity and cytotoxicity of a platinum(IV) complex derived from capsaicin.

Platinum-based anticancer drugs constitute the cornerstone of chemotherapy for various cancers. Although cytotoxic agents are considered to have immunosuppressive effects, increasing evidence suggests that some cytotoxic compounds can effectively stimulate the antitumor immune response by inducing a special type of apoptosis called immunogenic cell death (ICD). A platinum(iv) complex (DCP) modified with the derivative of synthetic capsaicin (nonivamide) was designed to elicit ICD. The complex exhibited high cytotoxicity against a panel of human cancer cell lines including pancreas (PANC-1), breast (MCF-7), and liver (HepG2) cancer cells, and osteosarcoma (MG-63) cells. In addition to causing DNA damage, DCP also triggered the translocation of calreticulin (CRT) as well as the release of ATP and HMGB1 protein in PANC-1 cells, thus manifesting an efficient ICD-inducing effect on cancer cells. Furthermore, the DCP-treated PANC-1 cell-conditioned culture medium promoted the release of IFN-γ and TNF-α to induce the immune response of human peripheral blood mononuclear cells, thereby increasing their cytotoxicity to cancer cells. Concurrently, the phagocytosis of PANC-1 cells by macrophages was also augmented by DCP. The results demonstrate that DCP is an effective inducer of ICD and a potential agent for chemoimmunotherapy of cancers.

Inhibiting Aß toxicity in Alzheimer's disease by a pyridine amine derivative.

Alzheimer's disease (AD) is a neurodegenerative disorder with no radical therapy. Aggregation of amyloid ß-peptide (Aß) induced by various factors is associated with pathogenesis of AD. A pyridine amine derivative, 3-bis(pyridin-2-ylmethyl)aminomethyl-5-hydroxybenzyltriphenylphosphonium bromide (PAT), is synthesized. The inhibition of self- and metal-induced Aß aggregation by PAT is confirmed by thioflavine T fluorescence, circular dichroism spectroscopy, and TEM. Western blot, RT-PCR and fluorescence imaging indicate that PAT can alleviate the Aß-induced paralysis, reduce the production of ROS, and protect the mitochondrial function in transgenic C. elegans. Genetic analyses indicate that heat shock protein is involved in the alleviation of Aß toxicity. PAT also inhibits the activity of acetylcholinesterase in C. elegans. Morris water maze test shows that the memory and cognitive ability of APP/PS1 AD model mice are significantly improved by PAT. Both in vitro and in vivo studies demonstrate that PAT is effective in counteracting Aß toxicity and ameliorating cognitive functions in AD mice, and therefore a potential lead compound of anti-AD drugs.

Alleviation of symptoms of Alzheimer's disease by diminishing Aß neurotoxicity and neuroinflammation.

Alzheimer's disease (AD) is one of the most prevailing neurodegenerative illnesses in the elderly. Accumulation of amyloid-ß peptide (Aß) and inflammation play critical roles in the pathogenesis and development of AD. Multi-target drugs may interdict the progress of AD through a synergistic mechanism. A neuromodulator, 2-((1H-benzo[d]imidazole-2-yl)methoxy)benzoic acid (BIBA), consisting of an Aß-targeting group and a derivative of anti-inflammatory aspirin was designed as a potential anti-AD agent. BIBA exhibits a remarkable inhibitory effect on the self- and metal-induced Aß aggregations and shows outstanding anti-inflammatory activity simultaneously. The neurotoxicity of Aß aggregates is attenuated, and the production of pro-inflammatory cytokines (PICs), such as IL-6, IL-1ß and TNF-α, in microglia stimulated by lipopolysaccharide (LPS) or Aß is reduced. Owing to the synergy between the inhibition of Aß oligomerization and downregulation of PICs, BIBA markedly prolongs the lifespan and relieves the Aß-induced paralysis of Aß-transgenic Caenorhabditis elegans, thus showing the potential to ameliorate the symptoms of AD through inhibiting Aß neurotoxicity and deactivating microglia. These findings demonstrate that both Aß aggregation and neuroinflammation are therapeutic targets for anti-AD drugs, and dual-functional agents that integrate anti-Aß and anti-inflammatory capabilities have great advantages over the traditional single-target agents for AD treatment.