TMJ-105, an extract of Carpesium cernuum, induced G2/M phase arrest and apoptosis via the JAK2/STAT3 axis and MAPKs signaling pathway in leukemia HEL cells.

Leukemia is a malignant tumor of the hematologic system. Studies have shown that cernuumolide J (TMJ-105), an extract of Carpesium cernuum, has anti-cancer effects, but the underlying mechanism is unclear. In this study, we investigated the effect of TMJ-105 on the proliferation of human leukemia HEL cells and its molecular mechanism. MTT analysis showed TMJ-105 had revealed that it shows significant IC50 in HEL cells at lower doses (1.79 ± 0.29 µmol/L) than in K562 cells (3.89 ± 0.80 µmol/L), and the suppression of HEL cell proliferation was time- and concentration-dependent. Meanwhile, TMJ-105 induced G2/M phase blockage, leading to DNA damage in HEL cells. TMJ-105 promoted HEL cells to release of reactive oxygen species (ROS) and changed mitochondrial membrane potential (MMP). Furthermore, TMJ-105 induced apoptosis by upregulating the cleaved-caspase9 and cleaved-caspase3 protein expression, while caspase pan inhibitor (Z-VAD-FMK) blocked the inhibition effect. Finally, TMJ-105 downregulated the phosphorylation of JAK2, STAT3 and Erk, and activated the phosphorylation of JNK and p38. Collectively, these results demonstrated that TMJ-105 inhibited proliferation of leukemia cells and the underlying mechanism via the JAK2/STAT3 axis and MAPKs signaling pathway. Based on these results, the present study suggested the sesquiterpene lactone TMJ-105 is a new chemotherapeutic agent for the treatment of leukemia.

Synergistic combination of isogarcinol isolated from edible fruits of Garcinia multiflora and dexamethasone to overcome leukemia glucocorticoid resistance.

Isogarcinol (ISO), a cytotoxic polycyclic polyprenylated acylphloroglucinol isolated from the edible fruits of Garcinia multiflora. However, synergistic combination of ISO and dexamethasone (DEX) to overcome leukemia glucocorticoid resistance has never been investigated. Therefore, in this study, the effects of ISO in combination with DEX was conducted on leukemia in vivo and glucocorticoid resistance in vitro. As a result, the combination of the two compounds could efficiently inhibit leukemia progression in mice and reverse DEX resistance in acute lymphoblastic leukemia (ALL) Jurkat cells. Significantly, our findings indicated that c-Myc may be a potential target of ISO, as it is involved in cell cycle arrest and apoptosis by the combination of ISO and DEX in Jurkat cells. Furthermore, western blot analysis revealed that ISO and DEX inhibits the PI3K/Akt/mTOR signaling pathway and promotes the nuclear translocation of glucocorticoid receptor (GR), which activates target genes NR3C1 and TSC22D3, leading to apoptosis in Jurkat cells. Hence, our results suggest that ISO, as a safe and effective food-derived agent, can enhance the anti-leukemia effects of DEX.

Integrating UPLC-HR-MS/MS, Network Pharmacology, and Experimental Validation to Uncover the Mechanisms of Jin'gan Capsules against Breast Cancer.

In the theory of traditional Chinese medicine (TCM), "liver-qi" stagnation and heat-induced toxicity represent the main etiologies of breast cancer. Recently, several TCMs with heat-clearing and detoxification efficacy have shown inhibitory effects on breast cancer. Jin'gan capsules (JGCs), initially approved to treat colds in China, are a heat-clearing and detoxification TCM formula. However, the anticancer activity of JGCs against breast cancer and its underlying mechanisms remain unclear. First, we assessed the antiproliferative activity of JGCs in breast cancer cell lines and evaluated their effects on cell apoptosis and the cell cycle by flow cytometry. Furthermore, we identified the potential bioactive components of JGCs and their corresponding target genes and constructed a bioactive compound-target interaction network by ultra-performance liquid chromatography-high-resolution tandem mass spectrometry (UPLC-HR-MS/MS) and network pharmacology analysis. Finally, the underlying mechanism was investigated through gene function enrichment analysis and experimental validation. We found that JGCs significantly inhibited breast cancer cell growth with IC50 values of 0.56 ± 0.03, 0.16 ± 0.03, and 0.94 ± 0.09 mg/mL for MDA-MB-231, MDA-MB-468, and MCF-7, respectively. In addition, JGC treatment dramatically induced apoptosis and S phase cell cycle arrest in breast cancer cells. Western blot analysis confirmed that JGCs could regulate the protein levels of apoptosis- and cell cycle-related genes. Utilizing UPLC-HR-MS/MS analysis and network pharmacology, we identified 7 potential bioactive ingredients in JGCs and 116 antibreast cancer targets. Functional enrichment analysis indicated that the antitumor effects of JGCs were strongly associated with apoptosis and the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway. Western blot analysis validated that JGC treatment markedly decreased the expression levels of p-JAK2, p-STAT3, and STAT3. Our findings suggest that JGCs suppress breast cancer cell proliferation and induce cell cycle arrest and apoptosis partly by inhibiting the JAK2/STAT3 signaling pathway, highlighting JGCs as a potential therapeutic candidate against breast cancer.