cucurbitacin I (JSI-124)

Moreover, the proportion of immunosuppressive cells including myeloid‑derived suppressor cells, T regulatory cells and M2‑polarized macrophages, decreased. These data suggested that CUIIa is a promising combination partner with DOX for liver cancer treatment, probably via triggering ICD and remolding the immune microenvironment.

Collectively, our findings emphasize that JSI-124 holds potential as a therapeutic agent for GBM by impeding cell cycle progression, inhibiting cell proliferation, and promoting apoptosis. As demonstrated by our in vitro experiments, these effects are mediated through modulation of key molecular targets.

These findings highlight the potential of cucurbitacin I as a therapeutic agent that targets M2-like macrophages to inhibit cancer cell metastasis. Our study provides novel insights into the intricate interplay among macrophage polarization, cucurbitacin I, and heme oxygenase-1, thereby opening new avenues for cancer treatment.

Recent studies have identified cucurbitacins as promising molecules for therapeutic innovation with broad versatility in immune response. Thus, cucurbitacin is a promising class of anticancer agents that can be used alone or in combination with chemotherapy and radiotherapy for the treatment of many types of cancer.Therefore, based on the research reports in the past five years at home and abroad, we further summarize and review the structural characteristics, chemical and biological activities, and studies of cucurbitacins based on the previous studies to provide a reference for further development and utilization of cucurbitacins.

Autophagy inhibitors, Chloroquine (CQ) and Bafilomycin A1 (Baf-A1), inhibited autophagy and sensitized RN5 and AB12 cells to JSI-124-induced apoptosis. Our data indicate that JSI-124 is a promising therapeutic agent for MPM treatment.

In this study, the anticarcinogenic effects of sorafenib-cucurbitacin D and sorafenib-cucurbitacin I combination on HepG2 cell line were investigated. The combined cucurbitacin-sorafenib applications inhibited the expression of proteins and genes involved in EGFR and PI3K/AKT/mTOR, Raf/MEK/ERK signaling pathways. Due to showing the synergetic effect of cucurbitacins with sorafenib and their targeting of similar signaling pathways reveal that their combination may increase the efficacy of sorafenib by suppressing angiogenic, metastatic and proliferative activity in HCC.

We screened top candidate drugs in DS-ALL and non-DS ALL patient samples in vitro, and tested FK866 and cucurbitacin I in vivo in mice xenografted with a DS-ALL patient sample. We have generated the first de novo mouse model and cell lines recapitulating DS-ALL, which we have employed in drug screens to identify novel therapeutic approaches. These studies suggest promising candidates for further study in DS-ALL and other high-risk ALL subtypes to reduce toxicity and improve outcomes.

Molecular docking was used to evaluate the strength of affinity of sinomenine to the target cysteinyl aspartate specific proteinase-3(caspase-3) and STAT3, and combined with CCK-8 assay to detect the changes in cell viability after combination with STAT3 inhibitor JSI-124 in combination with CCK-8 assay...Therefore, sinomenine can inhibit the proliferation and invasion of human hepatocellular carcinoma cells and induce apoptosis, and the mechanism may be attributed to the activation of caspase-3 signaling and inhibition of the Akt/mTOR/STAT3 pathway. This study can provide a new reference for the in-depth research and clinical application of sinomenine and is of great significance to further promote the scientific development and utilization of sinomenine.

This observation correlated with significantly decreased levels of key downstream proteins (phosphorylated ERK and mTOR) of the EGFR pathway in knockout cells compared with controls when treated with CIEAs. Collectively, our findings indicate that Sia deacetylation renders lung and colon cancer cells susceptible to EGFR therapeutics and provide insights for future therapeutic interventions.

Based on these gene signatures, we investigated 3 small compounds, namely cucurbitacin I, BMS-754807, and PHA-793887 as potential candidates for the treatment of cancer. Future studies on the mechanisms associated with the revealed gene signatures and anticancer effects of these three small compunds would allow scientists to develop therapeutic approaches to combat cancer. This research contributes to the evaluation of mechanisms and gene signatures that either limit or cause cancer, and to the development of new cancer therapies by establishing a link between regeneration and carcinogenesis.

These findings revealed that PGRN promote the progression of PTC through the JAK2-STAT3/4 pathway, and PGRN could be served as a potential therapeutic target for PTC.

Consistently, results of flow cytometry and AO/EB staining demonstrated that the growth-suppressive effect of CuIIb was mediated by cell cycle arrest in G2/M phase and robust induction of cell apoptosis, which was further confirmed by immunoblotting and mitochondrial membrane potential (ΔΨm) analysis. Collectively, the results presented herein indicated that CuIIb exhibited anticancer activity on bladder cancer which may be a potential candidate for improving bladder cancer outcomes.

DNA breaks are formed as a result of this effect. CuI, by reducing cell proliferation and promoting apoptosis, was found to have potential as a chemotherapeutic agent of hepatocellular carcinoma.

Apoptotic activity of Etanison and Acetison was demonstrated in HeLa, due to the presence of caspase-9 and caspase-3 in western blot assays. Likewise, both the phytopreparations and CIIb showed inhibition of Nrf2, associating apoptotic activity with the inhibition of the GST transcription factor. In this sense, the phytopreparations of I. sonorae, as well as their derivatives, have the potential to obtain and develop anticancer products.

Our results proved that cucurbitacin B might be a potential candidate agent for adjuvant therapy in the process of CRC growth and metastasis.

The Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway inhibitor cucurbitacin I suppressed the promotive effects of HIF-3α overexpression on cell proliferation, invasion and TAK2/STAT3 pathway. Finally, OS cell line MG-63 transfected with HIF-3α short hairpin RNA (HIF-3α shRNA) were subcutaneously injected into nude mice, and the results found that HIF-3α knockdown significantly inhibited the xenograft tumor growth of OS in vivo. In conclusion, this study reveals that HIF-3α promotes OS progression in vitro and in vivo by activating KDM3A-mediated SOX9 promoter demethylation, which may provide a potential therapeutic mechanism for OS.

RN5 cells were pretreated with 3-methyladenine (2.5 mM) or chloroquine (50 µM) for 1h, and then coincubation with JSI-124 for another 24 h. Levels of protein expression were analyzed by western blot using antibodies against caspase 3, PARP, MAP1LC3B-II, p-mTOR/p-p70S6K and p-JAK2/p-STAT3. STAT3 inhibitor JSI-124 induces protective autophagy in RN5 murine mesothelioma cells through mTOR/p70S6K signaling pathway, suggesting that JSI-124 may be a potential therapeutic strategy for MPM.

The Hedgehog inhibitor (Vismodegib), Notch inhibitor Gamma Secretase Inhibitor (GSI), and Signal Transducer and Activator of Transcription 3 (STAT3) inhibitor Cucurbitacin I (JSI-124) were added separately into the co-culture system of A549 cancer cell with THP-1-derived macrophages. These results suggested that co-culturing A549 cells with THP-1-derived macrophages could induce the stemness of A549 cells via multiple pro-tumorigenic pathways. Thus, inhibition of the interaction between macrophages and lung cancer stem cells may be a viable target for lung cancer treatment in the future.

Together, these findings indicate that JSI-124-dependent inhibition of STAT3 could be of great therapeutic value for the treatment of breast cancer through targeting cancer cells as well as their growth supportive stromal fibroblasts and blood vessels. This could pave the path to developing a precise CAF-targeted anticancer therapy.

We show that both cucurbitacins decrease viability and cause apoptosis in these cell lines, although HuT-78 was more affected than SeAx (IC of 17.38 versus 22.01 μM for cucurbitacin E and 13.36 versus 24.47 μM for cucurbitacin I)...Furthermore, while JAK2 inhibition leads to decreased viability in SeAx cells (IC of 9.98 and 29.15 μM for AZD1480 and ruxolitinib respectively), both JAK1 and JAK3 do not...Nevertheless, a role of STAT5 and JAK2 cannot be excluded and should be explored further. This knowledge could contribute to the development of effective therapies for CTCL and other malignancies involving dysfunction of the JAK/STAT pathway.

Apoptosis was involved in the process of cucurbitacin I‑induced cell death, with an increase observed in cleaved‑caspase 3 and BAX, and a decrease in Bcl‑2...In brief, these results suggested that cucurbitacin I induced cell death through oxidative stress and the p190B‑Rac1 signaling axis in SKVO3 cells. The results may provide novel evidence for the treatment of ovarian cancer.