picropodophyllin (AXL1717)

According to the results, 17Beta-Hydroxywithanolide K and Ginkgolide A demonstrated strong binding affinity to IGF-1R (-9.4 Kcal/mol) and KRAS (-6.9 Kcal/mol), respectively, compared to the synthetic inhibitors Picropodophyllin (-7.7 Kcal/mol) and Sotorasib (-5.9 Kcal/mol). Overall, 17Beta-Hydroxywithanolide K and Ginkgolide A have potential as natural therapeutic agents for the treatment of lung cancer. However, additional in vitro and in vivo experiments are needed to validate these computational results.

From these, 15 bioactive compounds, including scopolin, picropodophyllin, catechin, yohimbine, squalene, campesterin, epicatechin, stigmasterol, p-coumaric acid, quinoline, methyl linoleate, methyl oleate, DTB-spdione, theobromine, and caffeine, were shortlisted for in silico docking studies...Based on enhanced fractionations, our study provides an expanded chemical profile of kola nut seeds and suggests that selected phytochemicals may serve as promising candidates for anticancer drug development. Further experimental validation is warranted to translate these insights into therapeutic applications.

IGF-1R inhibition was performed by picropodophyllin (PPP), an IGF-1R inhibitor, or by shRNA-mediated RNA silencing. Further investigation showed that BMI1 knockdown in A400 cells resulted in decreased IGF-1R phosphorylation, whereas BMI1 overexpression in A549 cells resulted in increased IGF-1R phosphorylation, indicating an interaction between these two proteins. A novel reciprocal regulatory relationship between IGF-1R and BMI1 has been identified in lung cancer cells, suggesting potential therapeutic strategies to combat pemetrexed resistance in lung cancer patients.

Furthermore, IGF1R inhibition by inhibitor effectively eliminated liver CSCs and inhibited the growth of tumors and metastasis in vivo. These findings uncover the important role of IGF1/IGF1R signaling in liver CSCs, and also provide a promising diagnostic marker as well as therapeutic intervention for HCC.

The natural IGF1R inhibitor PPP induced ferroptosis through blockage of PI3K/AKT/NRF2 signaling pathway and subsequent inhibition of downstream gene expression of SLC7A11 and SLC40A1 in hepatocellular carcinoma. Consequently, our findings provide a novel action and mechanism of PPP, as well as offer innovative and promising ferroptosis-inducing agents for the clinical treatment of HCC.

In the cell co-culture system, HBx/IGF-1 signaling in HCC cells promoted Treg cells expansion, IL-10 secretion, and infiltration, which was blocked by the IGF-1R inhibitor picropodophyllin...IGF-1/IGF-1R signaling plays an important role in the communication between HCC cells and Treg cells. Targeting WDR or IGF-1/IGF-1R would be beneficial for the treatment of HCC.

Immunofluorescence staining revealed that this combination also significantly increased E-cadherin expression, by 1.37- and 1.63-fold, respectively (P<0.05), indicating the role of PPP in enhancing epithelial characteristics and reducing EMT-related drug resistance. These findings highlight the potential for combining PPP with OX to enhance the cytotoxic and anti-metastatic effects of OX in chemo-resistant CRC cells, thus offering a promising strategy for overcoming drug resistance and improving patient outcomes in CRC treatment.

We developed a novel new squamous cell lung carcinoma cell line, OMUL-1, that expresses IGF1R and PD-L1.

Conversely, hypoxia and the prolyl hydroxylase inhibitor Roxadustat raised TIMAP mRNA and protein levels by inhibiting the BMP9 pathway...Cultured breast cancer E0771 cells released mediators that raised TIMAP expression in endothelial cells, effects that were inhibited by the VEGF inhibitor Sunitinib in conjunction with the IGF-1 inhibitor Picropodophyllin. In the mouse E0771 breast cancer model in vivo, tumor growth and tumor angiogenesis were markedly attenuated in TIMAP deficient, compared to wild-type littermates. These findings indicate that TIMAP plays a critical pro-angiogenic function during tumor angiogenesis in vivo, likely through hypoxia-driven inhibition of the BMP9 pathway and through elaboration of angiogenic growth factors by tumor cells.

Surface plasmon resonance and immunoprecipitation assay validated that PPP directly targets HSP90 and disrupts the binding of HSP90 to AKT, thereby suppressing GC cell proliferation. Thus, our study revealed that PPP may be a promising therapeutic compound for GC treatment.

P1/2, N=10, Terminated, Rush University Medical Center | N=30 --> 10 | Unknown status --> Terminated; Investigator went to another institution.