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Proscillaridin A induces apoptosis and suppresses non-small-cell lung cancer tumor growth via calcium-induced DR4 upregulation.

ABSTRACT: Non-small-cell lung cancer (NSCLC) is the predominant histological type of lung cancer and is characterized by the highest mortality and incidence rates among these types of malignancies. Cardiac glycosides, a class of natural products, have been identified as a potential type of chemotherapeutic agent. This study aims to investigate the anti-cancer effects and the mechanisms of action of Proscillaridin A (P.A) in NSCLC cells. In vitro sodium-potassium pump (Na+/K+ ATPase) enzyme assays indicated that P.A is a direct Na+/K+ ATPase inhibitor. P.A showed potent cytotoxic effects in NSCLC cells at nanomolar levels. Treatment mechanism studies indicated that P.A elevated Ca2+ levels, activated the AMPK pathway and downregulated phosphorylation of ACC and mTOR. Subsequently, P.A increased death receptor 4 (DR4) expression and downregulated NF-κB. Interestingly, P.A selectively suppressed EGFR activation in EGFR mutant cells but not in EGFR wild-type cells. In vivo, P.A significantly suppressed tumor growth in nude mice compared to vehicle-treated mice. Compared with the Afatinib treatment group, P.A displayed less pharmaceutical toxicity, as the body weight of mice treated with P.A did not decrease as much as those treated with Afatinib. Consistent changes in protein levels were obtained from western blotting analysis of tumors and cell lines. Immunohistochemistry analysis of the tumors from P.A-treated mice showed a significant suppression of EGFR phosphorylation (Tyr 1173) and reduction of the cell proliferation marker Ki-67. Taken together, our results suggest that P.A is a promising anti-cancer therapeutic candidate for NSCLC.

SUBMITTER: Li RZ

PROVIDER: S-EPMC5999972 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Aloe-Emodin Induces Breast Tumor Cell Apoptosis through Upregulation of miR-15a/miR-16-1 That Suppresses BCL2.

Project description:Purpose:Aloe-emodin (AE) is a natural compound derived from aloe vera and palmatum rhubarb and shows anticancer activities in various cancers. Bcl-2 family is the main regulator of cell death or cell survival. This study describes the effects of AE on proliferation of breast tumor (BT) cells. Methods:MCF-10A, MCF-10AT, MCF-7, and MDA-MB-231 cell lines were exposed to AE. Cell proliferation and apoptosis were assessed by CCK-8 and flow cytometry. Protein levels were measured by Western blotting. The levels of mRNA and miRNA were examined by RT-PCR. Bioinformatics was applied to screen miRNAs that bind to 3'-UTR of mRNA. Results:The results showed that AE selective activity inhibited the proliferation and induced apoptosis of MCF-10AT and MCF-7 cells but exhibited no significant inhibition in MCF10A and MDA-MB-231 cells. Mechanistically, AE dose-dependently decreased the protein expression of Bcl-2 and Bcl-xl, while it increased Bax protein expression in MCF-10AT and MCF-7 cells. The levels of Bcl-xl and Bax mRNA were altered by AE treatment, which was consistent with the protein expression results. However, Bcl-2 mRNA levels were not affected in either cell line, suggesting that AE may modulate the protein translation of Bcl-2 through miRNAs. In all candidate miRNAs that bind to 3'-UTR of Bcl-2, miR-15a and miR-16-1 were dose-dependently downregulated by AE. Moreover, inhibition of miR-15a/16-1 could eliminate the inhibition of MCF-10AT and MCF-7 cells growth by AE and could reverse the downregulation of AE-induced Bcl-2 protein level. Conclusion:Our research provides an important basis that AE induces BT cell apoptosis through upregulation of miR-15a/miR-16-1 that suppresses BCL2.

| S-EPMC7073502 | biostudies-literature

Proscillaridin A Promotes Oxidative Stress and ER Stress, Inhibits STAT3 Activation, and Induces Apoptosis in A549 Lung Adenocarcinoma Cells.

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| S-EPMC5821950 | biostudies-literature

6,6'-Bieckol induces apoptosis and suppresses TGF-β-induced epithelial-mesenchymal transition in non-small lung cancer cells.

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| S-EPMC9476679 | biostudies-literature

STAT5 inhibition induces TRAIL/DR4 dependent apoptosis in peripheral T-cell lymphoma.

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| S-EPMC5908286 | biostudies-literature

Yinzhihuang injection induces apoptosis and suppresses tumor growth in acute myeloid leukemia cells.

Project description:BackgroundThe unmet needs in treating acute myeloid leukemia(AML) promote us to look for more effective and less toxic therapies. In this study, we discovered that Yinzhihuang injection(YZHI), a traditional Chinese patent medicine for hepatitis treatment, suppressed the growth of AML cells.MethodAnti-proliferative activities of YZHI were measured by CCK-8 assay. Cell cycle arrest was evaluated by PI staining, and apoptosis was evaluated by annexin V/PI staining. To explore the cell cycle arrest and cell death mechanism induced by YZHI, we assessed a series of assays, including measurements of the protein expression and cellular ATP. The anti-tumor activity was further demonstrated in nude mice.ResultsFlow cytometric and biochemical analysis revealed that YZHI caused cell cycle arrest and induced apoptosis in the AML HL-60 cells. Mechanistically, YZHI activated AMPK by promoting phosphorylation of the kinase. The active AMPK negatively regulated the downstream target mTORC1, leading to the inhibition of cell proliferation and induction of apoptosis. Pretreatment with the AMPK inhibitor compound C rescued YZHI induced apoptosis and partially restored cell proliferation of HL-60. Consistent with the data in vitro, YZHI obviously suppressed subcutaneous xenograft growth in nude mice.ConclusionsIn a word, our data suggest that YZHI can be repurposed for the treatment of AML, which is worthy of further clinical evaluation.

| S-EPMC10564230 | biostudies-literature

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| S-EPMC7073031 | biostudies-literature

Jinfukang induces cellular apoptosis through activation of Fas and DR4 in A549 cells

Project description:The traditional Chinese medicine Jinfukang (JFK) has been shown as a valuable drug for the non-small cell lung cancer (NSCLC) patients. Although clinically effective, the underlining mechanism remains unclear. Here, we performed RNA-seq assays for study the antitumor mechanisms of JFK ethanol extract on lung cancer cell line A549.

2016-05-02 | E-MTAB-3592 | biostudies-arrayexpress

Modification of Mcl-1 alternative splicing induces apoptosis and suppresses tumor proliferation in gastric cancer.

Project description:Splicing dysregulation, which leads to apoptosis resistance, has been recognized as a major hallmark for tumorigenesis and cancer progression. Targeting alternative splicing by either increasing pro-apoptotic proteins or inhibiting anti-apoptotic proteins in tumor cells may be an effective approach for gastric cancer (GC) therapy. However, the role of modulation of alternative splicing in GC remains poorly understood. In this study, to the best of our knowledge, the unbalanced expression of the myeloid cell leukemia-1 (Mcl-1) splicing variants, Mcl-1L and Mcl-1S, was identified in GC patients for the first time. Increasing anti-apoptotic Mcl-1L and decreasing pro-apoptotic Mcl-1S expression levels were correlated with tumor proliferation and poor survival. In vitro data showed that a shift in splicing from Mcl-1L to Mcl-1S induced by treatment with Mcl-1-specific steric-blocking oligonucleotides (SBOs) efficiently decreased Mcl-1L expression, increased Mcl-1S expression, and accelerated tumor cell apoptosis in a dose-dependent manner. Additionally, mouse xenotransplant models confirmed that modification of Mcl-1 alternative splicing increased tumor cell death and suppressed tumor proliferation. This study demonstrated that the modification of Mcl-1 splicing might stimulate the pro-apoptotic factor and inhibit the anti-apoptotic protein to induce significant apoptosis. Thus, this finding provided a strategy for cancer therapy, according to which SBOs could be used to change the Mcl-1 splicing pattern, thereby inducing apoptosis.

| S-EPMC7732305 | biostudies-literature

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| S-EPMC5561576 | biostudies-other

Small-molecule inhibition of APE1 induces apoptosis, pyroptosis, and necroptosis in non-small cell lung cancer.

Project description:Apurinic/apyrimidinic endonuclease 1 (APE1) plays a critical role in the base excision repair (BER) pathway, which is responsible for the excision of apurinic sites (AP sites). In non-small cell lung cancer (NSCLC), APE1 is highly expressed and associated with poor patient prognosis. The suppression of APE1 could lead to the accumulation of unrepaired DNA damage in cells. Therefore, APE1 is viewed as an important marker of malignant tumors and could serve as a potent target for the development of antitumor drugs. In this study, we performed a high-throughput virtual screening of a small-molecule library using the three-dimensional structure of APE1 protein. Using the AP site cleavage assay and a cell survival assay, we identified a small molecular compound, NO.0449-0145, to act as an APE1 inhibitor. Treatment with NO.0449-0145 induced DNA damage, apoptosis, pyroptosis, and necroptosis in the NSCLC cell lines A549 and NCI-H460. This inhibitor was also able to impede cancer progression in an NCI-H460 mouse model. Moreover, NO.0449-0145 overcame both cisplatin- and erlotinib-resistance in NSCLC cell lines. These findings underscore the importance of APE1 as a therapeutic target in NSCLC and offer a paradigm for the development of small-molecule drugs that target key DNA repair proteins for the treatment of NSCLC and other cancers.

| S-EPMC8131371 | biostudies-literature

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