CBT-1 (tetrandrine)

P4, N=0, Withdrawn, Peking University Third Hospital | N=414 --> 0 | Not yet recruiting --> Withdrawn

We further revealed that the combination of TET with αPD-1 monoclonal antibody (αPD-1 mAb) yields significant anti-cancer effects by promoting CD8+ T cell infiltration and enhancing its cell-killing effect, which in turn reduced the growth of tumors and prolonged survival of NSCLC mice. Therefore, TET effectively eliminates NSCLC cells and enhances immunotherapy efficacy through the activation of the STING pathway, and combining TET with anti-PD-1 immunotherapy deserves further exploration for applications.

The results of treating subcutaneous xenograft tumors with a combination of tetrandrine and chloroquine validated that autophagy inhibition enhances the toxicity of tetrandrine against pancreatic cancer in vivo. Altogether, our study demonstrates that tetrandrine induces cytoprotective autophagy in pancreatic cancer cells. Inhibiting tetrandrine-induced autophagy promotes the accumulation of ROS and enhances its toxicity against pancreatic cancer.

This study is expected to provide valuable references and potential drugs for future research and treatment of COVID-19 and ICC.

BMSC can promote the drug resistance of leukemia cells, and TET may reverse the BMSC-mediated drug resistance via inhibiting IL-6/STAT3 signaling pathway.

Moreover, LPS activate NF-κB signal pathway, while Tet efficiently inhibited this effect.Furthermore, injection of Tet did not damage theroutineblood, liver and kidney. Retrobulbar injection of Tet significantly alleviatedLPS-induced uveitisand optic nerve injuryof rats by activating gliocyte and NF-κB signaling pathway.

Subsequent single-cell sequencing data confirmed that these four genes were distributed in epithelial cells, and SMR analysis revealed the causal relationship between CCNA2 and CCNB1 and the development of NSCLC. The final molecular docking and drug experiments showed that CCNA2 and CCNB1 are key targets for tetrandrine in the treatment of NSCLC.

The metabolism features of tetrandrine and its potential antitumor mechanism were summarized, providing data for further pharmacological validation.

Of great interest, tetrandrine stabilizes DR4/DR5 protein via impairing ubiquitination-mediated protein degradation, thereby allowing a synergy with MAPK inhibition in inducing apoptosis in KRAS-mutant PDAC. Our findings identify a new combinatorial approach for treating KRAS-mutant PDAC and highlight the role of TRAIL-DR4/DR5 axis in dictating the therapeutic outcome in KRAS-mutant PDAC.

P4, N=414, Not yet recruiting, Peking University Third Hospital | Trial completion date: Dec 2024 --> Dec 2025 | Initiation date: Jan 2023 --> Dec 2023 | Trial primary completion date: Dec 2024 --> Dec 2025

Dihydroartemisinin (DHA) and tetrandrine (TET) were co-delivered for the first time to treat DOX resistance of breast cancer with multi-pathway mechanism. With the DOX resistance reversing ability increased, the inhibition effect of DHA-TET pH-sensitive LPs on both MCF-7/ADR cells and MCF-7 cells was significantly enhanced; meanwhile, the toxicity on cardiac cell (H9c2) was lowered. Ferroptosis induced by the DHA was investigated showing that the intracellular reactive oxygen species (ROS) and lipid peroxidation were increased to promote the synergistic effect through the due-loaded nano-carrier, providing a promising alternative for future clinical application.

We highlighted that miR-638 suppresses cervical cancer progression by inhibiting NCAPG2 under tetrandrine treatment.

Finally, in our vivo experiment, we discovered that TetC significantly slowed the growth rate of subcutaneous transplanted A549 cells, ultimately proving to be biosafe. In conclusion, our study first identified the mechanism by which TetC-induced ferroptosis in LUAD via SLC7A11/GPX4 signaling.

Therefore, our study proposes the use of tetrandrine analogs with the aim of improving sorafenib therapy. Also, our data also allow us to suggest that TPCs may be a new target in anticancer therapies.

Indeed, diacerein, an IL1B inhibitor, strongly blocked Fli-1-induced leukemia in mice. Moreover, the HDC inhibitor, tetrandrine, suppressed HDC transcription by directly binding to and inhibiting the FLI1 DNA binding domain, and like other FLI1 inhibitors, tetrandrine strongly suppressed cell proliferation in culture and leukemia progression in vivo. These results suggest a role for the transcription factor FLI1 in inflammation signaling and leukemia progression through HDC and point to the HDC pathway as potential therapeutics for FLI1-driven leukemia.

During chemotherapy of patients with colon cancer, tetrandrine may inhibit the expression of TNF-α in cancer tissues and blood, reduce the release of inflammatory factors and chemokines and decrease cancer cell proliferation. These findings provide a theoretical basis for the treatment of colon cancer in the clinic.

TAS and the main alkaloid components exert anticancer activity in NSCLC by regulating tumor cell proliferation and apoptosis. Therefore, TAS and the main alkaloid components have the potential to be used as multi-targeted drugs for lung cancer treatment.

The results of this study suggest that tetrandrine could effectively inhibit breast cancer stem cell characteristics and the EMT process via the SOD1/ROS signaling pathway. Therefore, tetrandrine can be considered a promising anti-TNBC agent.

In animal experiments, tumor growth was inhibited by Tet administration in a dose-dependent manner. In conclusion, the current data indicated that Tet had a critical effect on inhibiting BGC-823 and MKN-45 cells proliferation, migration, invasion and tumor growth via regulating PI3K/AKT/mTOR signaling pathway, suggesting that Tet might be a potential treatment for GC.

Phytochemicals could target the mitochondria in the treatment of gastric cancer, providing potential directions and evidence for clinical translation. Drug discovery focused on phytochemicals has great potential to break barriers in cancer treatment.

TGF-β1-induced human lung adenocarcinoma A549 cells were used as an in vitro experimental verification model, taking dexamethasone (Dex) as the positive control, to verify the effects of Tet on the mRNA expression of the candidate targets. Combined with the results of theoretical calculation and experimental verification, and considering the roles of these targets in the pathogenesis of PF, Tet might antagonize PF by acting on PDPK1 and RAC1. The results of this study will provide scientific reference for the prevention and clinical diagnosis and treatment of PF.

Further study showed that 16 effectively inhibited the proliferation, migration, and tube formation of umbilical vein endothelial cells, manifesting in a potent anti-angiogenesis effect. Overall, these results revealed the potential of 16 as a promising candidate for further preclinical studies.

Tetrandrine also had abilities to up-regulate not only the expression of GRP78 and ATF-4 but also the phosphorylation of eIF-2α in SW872 cells. In summary, these results demonstrated that tetrandrine has strong growth-suppressive and apoptosis-inducing effects on SW872 cells, which are mediated through control of the intrinsic caspase pathway, down-regulation of XIAP and STAT-3, and triggering ER stress.

Further studies showed that TetC significantly suppressed the expression of glutathione peroxidase 4 (GPX4) and ferritin heavy chain 1 (FTH1) but increased the expression of nuclear receptor coactivator 4 (NCOA4) in MCF7 and MDA-MB-231 cells even in the presence of erastin or Ras-selective lethal 3 (RSL3). Collectively, we showed novel data that ferroptosis was a major form of TetC-induced cell death. Moreover, TetC-induced ferroptotic cell death was achieved via suppressing GPX4 expression and activating NCOA4-mediated ferritinophagy in BC cells.

Furthermore, at a dose of 25 mg/kg/day, TTD reduced tumor growth in an athymic nude mouse xenograft model bearing Panc-1 cells. These data show that TTD is an NR4A1 antagonist and that modulation of the NR4A1-mediated pro-survival pathways is involved in the antitumor effects of TTD.

Furthermore, the hematoxylin and eosin (H & E) staining of kidney, liver, and spleen tissues showed no significant difference between the TET-treated and control groups. Overall, these observations demonstrated that TET suppressed subcutaneous tumor growth in a nude-mice model via the induction of cell apoptosis.

This study provides a cell screening model for identification of potential individualized treatment drugs for patients with uveal melanoma with SF3B1 mutation.

The plate cloning assay and soft agar colony formation assay showed that Tet weakened the colony formation of LN229 cells in vitro; cytometry assay showed that Tet blocked cells in the G_1 phase and promoted cell apoptosis; scratch and Transwell assays proved that Tet inhibited the migration and invasion of LN229 cells; Western blot results showed that Tet down-regulated the expression levels of CDK2, CDK6, cyclin D1, cyclin E1, snail, slug, vimentin, and N-cadherin, while up-regulated the level of E-cadherin. The results indicate that Tet has a certain inhibitory effect on the proliferation, migration, and invasion of LN229 glioblastoma cells, and such effect may be related to the participation of Tet in the regulation of c-Myc/p27 axis and snail signaling pathway.

Several significant genes that should be integrated into future mechanistic models of the WNT pathway are DVL3, FZD5, RAC1, ROCK2, GSK3B, CTB2, CBT1, and PRKCA. Thus, the study demonstrates that using mechanistic information in combination with machine learning can identify novel features (genes and proteins) that are important for explaining the STN heterogeneity between patients and their association to clinical outcomes.

Furthermore, the regulatory effect of TET on OS cells and related signaling pathways was verified again in vivo. Our findings suggest that the anticancer function of TET on human OS may be mediated by its targeting of multiple signaling pathways and that TET may be used as a single drug or in combination with other drugs during the treatment of OS.

In addition, tetrandrine restored E-cadherin gene promoter activity. The findings of the present study suggested that tetrandrine may inhibit EMT in IL-6-stimulated HCT116 cells; therefore, it may represent a potential drug for CRC.

TET promotes apoptosis by inhibiting the PI3K/Akt/mTOR signaling pathway and promotes autophagy via up-regulating the AMPK signaling pathway to play an anti-tumor effect in GEM-resistant pancreatic cancer cells, which represents a new therapeutic strategy for the treatment of GEM-resistant pancreatic cancer.

The results were further confirmed by immunofluorescence assays. Based on bioinformatic analysis and experimental verification, our findings demonstrated that tetrandrine exerted tumour-suppressive effects on EC by regulating the PI3K/Akt signalling pathway.

Tet as a monotherapy inhibits TAM-R cells. Tet potentiates the pro-apoptotic effect of TAM via inhibition of autophagy.

In addition, compound 4g inhibited the phosphorylation of PI3K, Akt and mTOR, suggesting a correlation between blocking the PI3K/Akt/mTOR pathway and the above antitumor activities. These results suggest that compound 4g may be a future drug for the development of new potential drug candidates against lung cancer.

The ratio of dead/live cells in each cell line treated with TET and CEP increased in a dose-dependent manner. Overall, the present study demonstrated that CEP had greater cell toxicity in 3D spheroids of breast cancer cells compared with TET, suggesting that CEP may have a stronger antitumor activity on TNBC spheroids compared with TET.

Further cell cycle profiling showed a nearly 50% reduction of the S-phase cells after tetrandrine treatment, suggesting that tetrandrine inhibited DNA synthesis as well as cell proliferation. At the molecular level, tetrandrine induced downregulation of Bcl-2 and simultaneous upregulation of Bax and caspase-3 as well as enhanced cell apoptosis.Our results demonstrated that tetrandrine inhibited the cell viability and proliferation of CD133 Hep-2 cells by reducing the number of cells in the S-phase of the cell cycle and enhancing cell apoptosis.

These results suggest that nM grade of MP potentiates the cytotoxic effect of TET possibly via regulation of NF-κB activation and "G0/G1 to S" phase transition in human T lymphoblastoid leukemia MOLT-4 cells. Combination of TET and MP may provide a new therapeutic strategy for relapsed T-ALL.

Our results showed that TET significantly repressed the cell mobility, migration, and invasion of NPC-TW 039 cells in vitro that involved in inhibiting RhoA, Ras accompanying with p38/MAPK signaling pathway. We conclude that TET may be the anticancer agents for nasopharyngeal carcinoma therapy in the future.

The mechanism underlying this effect might be mediated by TET-upregulated Caspase-3, Bax, and Bid and downregulated by Bcl-2, Survivin, and PARP. Taken together, this study supported the fact that TET is a promising therapeutic agent for the treatment of TNBC, thereby providing experimental evidence for its use in the treatment of breast cancer.