Recently, there has been renewed interest in metabolic therapy for cancer, particularly in amino acid deprivation by enzymes. L-asparaginase was approved for the treatment of acute lymphoblastic leukemia by the U.S. Food and Drug Administration. Arginine deiminase and recombinant human arginase have been developed into clinical trials as potential cancer therapeutic agents for the treatment of arginine-auxotrophic tumors. Moreover, other novel amino acid degrading enzymes, such as glutaminase, methionase, lysine oxidase, phenylalanine ammonia lyase, have been developed for the treatment of malignant cancers. One of the greatest obstacles faced by anticancer drugs is the development of drug resistance, which is reported to be associated with autophagy. Autophagy is an evolutionarily conserved catabolic process that is responsible for the degradation of dysfunctional proteins and organelles. There is a growing body of literature revealing that, in response to metabolism stress, autophagy could be induced by amino acid deprivation. The manipulation of autophagy in combination with amino acid degrading enzymes is actively being investigated as a potential therapeutic approach in preclinical studies. Importantly, shedding light on how autophagy fuels tumor metabolism during amino acid deprivation will enable more potential combinational therapeutic strategies. This study summarizes recent advances, discussing several potential anticancer enzymes, and highlighting the promising combined therapeutic strategy of amino acid degrading enzymes and autophagy modulators in tumors

Nowadays, chemotherapy is still the main effective treatment for cancer. Herb prescriptions containingPogostemon cablin Benth(also known as “Guang-Huo-Xiang”) have been widely used in Chinese medicine today. In our research, we found that patchouli alcohol, a compound isolated from the oil ofPogostemon cablin Benth, exerted antitumor ability against human lung cancer A549 cells ability bothin vitroandin vivo. MTT assay was used to assess cell viability. Hoechst 33342 staining and TUNEL cover glass staining provided the visual evidence of apoptosis. Caspase activity measurement showed that patchouli alcohol activated caspase 9 and caspase 3 of mitochondria-mediated apoptosis. Consistently, patchouli alcohol inhibited the xenograft tumorin vivo. Further investigation of the underlying molecular mechanism showed that MAPK and EGFR pathway might contribute to the antitumor effect of patchouli alcohol. Our study proved that patchouli alcohol might be able to serve as a novel antitumor compound in the clinical treatment of lung cancer.

Purpose: Poor antidiabetic medication adherence remains a great barrier to effective diabetes self-management among aging adults. This study investigates the mediation and moderation effects of self-efficacy on the relationship between medication beliefs and adherence in elderly patients with type 2 diabetes. Methods: This cross-sectional study evaluated a sample of 309 hospitalized elderly patients who completed the assessment of medication beliefs, self-efficacy for medication uses and medication adherence in a tertiary hospital in Shanghai, China. A bootstrapping sampling method and hierarchical moderator regression analysis were used to verify the hypothesis of mediation and moderation effects of self-efficacy on the relationship between medication beliefs and adherence. Results: Self-efficacy for medication use acted as a moderator (B=− 0.063, t=− 2.215, p=0.028) and partial mediator (CI_{total effect}=4.5– 16.63, p=0.001; CI_indirect=1.524– 5.323, p=0.014; CI_direct=2.151– 11.817, p=0.001) on the relationship between general harm medication beliefs and medication adherence. Participants with lower general harm medication beliefs may develop higher self-efficacy, which, in turn, results in a higher level of medication adherence, and higher self-efficacy may attenuate the negative effect of high general harm medication beliefs on medication adherence. Conclusion: Self-efficacy for medication use not only mediated the relationship between general harm beliefs about medication and medication adherence, but moderated it negatively. The findings of this study indicate an opportunity to improve the prognosis of elderly Chinese patients with type 2 diabetes through improved medication adherence by strengthening factors such as self-efficacy for appropriate medication use and general harm beliefs about medication.

Son of sevenless homolog 1 (SOS1) is an essential guanine nucleotide exchange factor for RAS that also plays a critical role in the activation of the small GTPase RAC mediated by BCR–ABL in leukemogenesis. Despite this, small-molecule inhibitors targeting SOS1 have shown limited efficacy in clinical trials for KRAS-mutant cancers, and their potential as a therapeutic approach for chronic myeloid leukemia (CML) remains largely unexplored. In this study, we developed a potent SOS1 proteolysis targeting chimera (PROTAC) SIAIS562055, which was designed by connecting a CRBN ligand to an analog of the SOS1 inhibitor BI-3406. SIAIS562055 exhibited sustained degradation of SOS1 and inhibition of downstream ERK pathways, resulting in superior antiproliferative activity compared with small-molecule inhibitors. SIAIS562055 also potentiated the activity of both KRAS inhibitors in KRAS-mutant cancers and ABL inhibitors in BCR–ABL–positive CML. In KRAS-mutant xenografts, SIAIS562055 displayed promising antitumor potency as a monotherapy and enhanced ERK inhibition and tumor regression when combined with KRAS inhibitors, overcoming acquired resistance. In CML cells, SIAIS562055 promoted the active uptake of BCR–ABL inhibitors by upregulating the carnitine/organic cation transporter SLC22A4. SIAIS562055 and BCR–ABL inhibitors synergistically enhanced inhibition of ABL phosphorylation and downstream signaling, demonstrating robust antitumor activities in both mouse xenografts and primary samples from patients with CML. In summary, this study suggests that PROTAC-mediated SOS1 degradation represents an effective therapeutic strategy for treating not only KRAS-mutant cancers but also BCR–ABL–harboring leukemia. Significance: The PROTAC SIAIS562055 sustainably degrades SOS1 and inhibits downstream ERK signaling, showing strong antiproliferative activity and synergistic effects with KRAS inhibitors in KRAS-mutant cancers and BCR–ABL inhibitors in chronic myeloid leukemia.

Trifolirhizin is a compound isolated from Sophora flavescens. It has been shown to exert cytotoxicity on several cancer cell lines. However, the underlying mechanism remains unknown. MKN45 cells were used as a research model. We assessed the cytotoxicity of trifolirhizin to MKN45 by MTT. Hoechst staining and TUNEL method were used to demonstrate apoptosis. Flow cytometry was used to determine cell cycle and ratio of apoptosis. Caspase activity assay was used to examine the activation of caspase cascade pathways. Western blotting was used to explore the protein levels. Consistently, trifolirhizin inhibited MKN45 xenograft tumor growth in vivo. Trifolirhizin caused a significantly decreased proliferation of MKN45 cells in a time- and dose-dependent manner, with IC50 values of 33.27±2.06 µg/ml at 48 h. Western blot assay manifested that trifolirhizin activated the EGFR-MAPK signaling pathways. This study indicated that trifolirhizin may be a therapeutic application in human gastric cancer therapy.