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The combination of SLC7A11 inhibitor and oridonin synergistically inhibits cervical cancer cell growth by decreasing the NADPH/NADP+ ratio

ABSTRACT: Oridonin, as a natural terpenoids isolated from traditional Chinese medicinal herb Rabdosia rubescens, exhibits anticancer activity against multiple cancers with the IC50 ranging from 10 ¦ÌM to 100 ¦ÌM. We observed that SLC7A11 inhibitor Imidazole ketone erastin (1 ¦ÌM) potently increase the anti-proliferative activity of oridonin at low concentrations. Preliminary investigation demonstrated that combination of Imidazole ketone erastin (1 ¦ÌM) and oridonin induced apoptosis and ferroptosis only in a fraction of cells. To explore the synergistic anti-tumor mechanism of combination of oridonin and Imidazole ketone erastin, second-generation transcriptome sequencing(RNA-seq) was utilized to determine the transcriptome change in Hela cells affected by oridonin and Imidazole ketone erastin. PCA analysis showed that the group of oridonin or Imidazole ketone erastin alone located near the control group, while the group of combination gathered far away from the control group, indirectly indicating that combination of oridonin and Imidazole ketone erastin had synergistic biology function.

ORGANISM(S): Homo sapiens

PROVIDER: GSE193751 | GEO | 2023/12/31

REPOSITORIES: GEO

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Project description:Purpose: We aimed to investigate the effect of several anti-leukemia drugs in combination with decitabine (DAC) on the proliferation of myeloid leukemia cells in vitro and in vivo, to select the most efficient combination group and explore associated mechanisms of these combination therapies. Experimental Design: After comparing with five anti-leukemia drugs in several different kinds of cell lines, the combination effect of idarubicin (IDA) with DAC was best. In vivo, by using microPET, TUNEL, and transmission electron microscopy, the inhibitory effects obtained by sequentially combining DAC with IDA, evidenced by evaluating tumor cell proliferation and cell apoptosis. Molecular studies were conducted using gene chip, which was used to explore associated pathways, and real-time quantitative reverse transcription-PCR, western blot and immunohistochemistry (IHC), used to assess regulation of Wnt/β-catenin pathway. Results: The sequential combination of DAC and IDA showed synergistic induction of cell death in U937, HEL, SKM-1 and cells isolated from AML patients. Importantly, the inhibition of tumor growth in the sequential combination group was found to be significantly higher than that of single drug group or control group in vivo. Moreover, sequential treatment with DAC and IDA induced apoptosis and depression of the Wnt/β-catenin pathway in both culture and animal studies. Conclusions: Our findings showed that sequentially combining decitabine with idarubicin had a synergistic anti-leukemia effect. These findings were attributed to demethylation of Wnt pathway inhibitors and downregulation of Wnt pathway nuclear targets observed in vitro and in vivo. After comparing with five anti-leukemia drugs in several different kinds of cell lines, the combination effect of idarubicin (IDA) with DAC was best. In vivo, by using microPET, TUNEL, and transmission electron microscopy, the inhibitory effects obtained by sequentially combining DAC with IDA, evidenced by evaluating tumor cell proliferation and cell apoptosis. Molecular studies were conducted using gene chip, which was used to explore associated pathways, and real-time quantitative reverse transcription-PCR, western blot and immunohistochemistry (IHC), used to assess regulation of Wnt/β-catenin pathway.

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The combination of SLC7A11 inhibitor and oridonin synergistically inhibits cervical cancer cell growth by decreasing the NADPH/NADP+ ratio

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