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Biflavonoids from Selaginella doederleinii as Potential Antitumor Agents for Intervention of Non-Small Cell Lung Cancer.

ABSTRACT: Four new biflavonoids (1-4) were isolated from Selaginella doederleinii together with a known biflavonoid derivative (5). Their structures contained a rare linker of individual flavones to each other by direct C-3-O-C-4''' bonds, and were elucidated by extensive spectroscopic data, including HRESIMS, NMR and ECD data. All isolates significantly inhibited the proliferation of NSCLC cells (IC50 = 2.3-8.4 μM) with low toxicity to non-cancer MRC-5 cells, superior to the clinically used drug DDP. Furthermore, the most active compound 3 suppressed XIAP and survivin expression, promoted upregulation of caspase-3/cleaved-caspase-3, as well as induced cell apoptosis and cycle arrest in A549 cells. Together, our findings suggest that 3 may be worth studying further for intervention of NSCLC.

SUBMITTER: Kang F

PROVIDER: S-EPMC8434134 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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Biflavonoids from Selaginella doederleinii as Potential Antitumor Agents for Intervention of Non-Small Cell Lung Cancer.

Kang Fenghua F Zhang Sha S Chen Dekun D Tan Jianbing J Kuang Min M Zhang Jinlin J Zeng Guangyuan G Xu Kangping K Zou Zhenxing Z Tan Guishan G

Molecules (Basel, Switzerland) 20210905 17

Four new biflavonoids (1-4) were isolated from Selaginella doederleinii together with a known biflavonoid derivative (5). Their structures contained a rare linker of individual flavones to each other by direct C-3-O-C-4''' bonds, and were elucidated by extensive spectroscopic data, including HRESIMS, NMR and ECD data. All isolates significantly inhibited the proliferation of NSCLC cells (IC50 = 2.3-8.4 μM) with low toxicity to non-cancer MRC-5 cells, superi ...[more]

PMID: 34500834

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Project description:Lung cancer can be divided into non-small cell lung cancer (NSCLC) and small cell lung cancer, and the incidence and mortality rate are continuously increasing. In many cases, lung cancer cannot be completely treated with surgery, so chemotherapy is used in parallel; however, the treatment often fails due to drug resistance. Therefore, it is necessary to develop a new therapeutic agent with a new target. The expression of sphingosine kinase promotes cancer cell growth and survival and induces resistance to chemotherapeutic agents. Sphingosine-1-phosphate (S1P), produced by sphingosine kinase (SK), has been shown to regulate cancer cell death and proliferation. PF-543, currently known as an SK inhibitor, has been reported to demonstrate low anticancer activity in several cancers. Therefore, in this study, a derivative of PF-543 capable of increasing anticancer activity was synthesized and its efficacy was evaluated by using an NSCLC cell line and xenograft animal model. Based on the cytotoxic activity of the synthesized compound on lung cancer cells, the piperidine forms (Compounds 2 and 4) were observed to exhibit superior anticancer activity than the pyrrolidine forms of the head group (Compounds 1 and 3). Compounds 2 and 4 showed inhibitory effects on SK1 and SK2 activity, and S1P produced by SK was reduced by both compounds. Compounds 2 and 4 demonstrated an increase in the cytotoxicity in the NSCLC cells through increased apoptosis. As a result of using an SK1 and SK2 siRNA model to determine whether the cytotoxic effects of Compounds 2 and 4 were due to SK1 and SK2 inhibition, it was found that the cytotoxic effect of the derivative was SK1 and SK2 dependent. The metabolic stability of Compounds 2 and 4 was superior compared to PF-543, and the xenograft experiment was performed using Compound 4, which had more excellent MS. Compound 4 demonstrated the inhibition of tumor formation. The results of this experiment suggest that the bulky tail structure of PF-543 derivatives is effective for mediating anticancer activity, and the results are expected to be applied to the treatment of NSCLC.

Project description:Introduction: Selaginella doederleinii Hieron is a traditional Chinese herbal medicine, the ethyl acetate extract from Selaginella doederleinii (SDEA) showed favorable anticancer potentials. However, the effect of SDEA on human cytochrome P450 enzymes (CYP450) remains unclear. To predict the herb-drug interaction (HDI) and lay the groundwork for further clinical trials, the inhibitory effect of SDEA and its four constituents (Amentoflavone, Palmatine, Apigenin, Delicaflavone) on seven CYP450 isoforms were investigated by using the established CYP450 cocktail assay based on LC-MS/MS. Methods: Appropriate substrates for seven tested CYP450 isoforms were selected to establish a reliable cocktail CYP450 assay based on LC-MS/MS. The contents of four constituents (Amentoflavone, Palmatine, Apigenin, Delicaflavone) in SDEA were determined as well. Then, the validated CYP450 cocktail assay was applied to test the inhibitory potential of SDEA and four constituents on CYP450 isoforms. Results: SDEA showed strong inhibitory effect on CYP2C9 and CYP2C8 (IC50 ≈ 1 μg/ml), moderate inhibitory effect against CYP2C19, CYP2E1 and CYP3A (IC50 < 10 μg/ml). Among the four constituents, Amentoflavone had the highest content in the extract (13.65%) and strongest inhibitory effect (IC50 < 5 μM), especially for CYP2C9, CYP2C8 and CYP3A. Amentoflavone also showed time-dependent inhibition on CYP2C19 and CYP2D6. Apigenin and Palmatine both showed concentration-dependent inhibition. Apigenin inhibited CYP1A2, CYP2C8, CYP2C9, CYP2E1 and CYP3A. Palmatine inhibited CYP3A and had a weak inhibitory effect on CYP2E1. As for Delicaflavone, which has the potential to develop as an anti-cancer agent, showed no obvious inhibitory effect on CYP450 enzymes. Conclusion: Amentoflavone may be one of the main reasons for the inhibition of SDEA on CYP450 enzymes, the potential HDI should be considered when SDEA or Amentoflavone were used with other clinical drugs. On the contrast, Delicaflavone is more suitable to develop as a drug for clinical use, considering the low level of CYP450 metabolic inhibition.

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Biflavonoids from Selaginella doederleinii as Potential Antitumor Agents for Intervention of Non-Small Cell Lung Cancer.

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Biflavonoids from <i>Selaginella doederleinii</i> as Potential Antitumor Agents for Intervention of Non-Small Cell Lung Cancer.

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