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Selective cytotoxicity, inhibition of cell cycle progression, and induction of apoptosis in human breast cancer cells by sesquiterpenoids from Inula lineariifolia Turcz.

ABSTRACT: Four new sesquiterpenoid dimers (lineariifolianoids E-H, 1-4), five new sesquiterpenoids (5-9), and seven known sesquiterpenoids (10-16) were isolated from the aerial parts of Inula lineariifolia Turcz. Their structures were determined by spectroscopic data analysis and X-ray diffraction studies. The compounds were then evaluated for their in vitro cytotoxicity against two human breast cancer cell lines (MCF-7 and MDA-MB-231) and one normal breast cell line (MCF-10A). Lineariifolianoid E (1) showed IC50 values of 1.56 ?M and 2.75 ?M against MCF-7 and MDA-MB-231, respectively. However, lineariifolianoid E demonstrated low toxicity to MCF-10A cells, which indicated a selective cytotoxicity for tumor cells. Further studies also presented that lineariifolianoid E had significant, dose-dependent effects on cell cycle progression and apoptosis in breast cancer cells.

SUBMITTER: Qin JJ

PROVIDER: S-EPMC4094229 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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Selective cytotoxicity, inhibition of cell cycle progression, and induction of apoptosis in human breast cancer cells by sesquiterpenoids from Inula lineariifolia Turcz.

Qin Jiang-Jiang JJ Jin Hui-Zi HZ Huang Ying Y Zhang Shou-De SD Shan Lei L Voruganti Sukesh S Nag Subhasree S Wang Wei W Zhang Wei-Dong WD Zhang Ruiwen R

European journal of medicinal chemistry 20130811

Four new sesquiterpenoid dimers (lineariifolianoids E-H, 1-4), five new sesquiterpenoids (5-9), and seven known sesquiterpenoids (10-16) were isolated from the aerial parts of Inula lineariifolia Turcz. Their structures were determined by spectroscopic data analysis and X-ray diffraction studies. The compounds were then evaluated for their in vitro cytotoxicity against two human breast cancer cell lines (MCF-7 and MDA-MB-231) and one normal breast cell line (MCF-10A). Lineariifolianoid E (1) sho ...[more]

PMID: 24044895

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Project description:BackgroundNon-small cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide. Pemetrexed, a multi-target folate antagonist, has demonstrated efficacy in NSCLC histological subtypes characterized by low thymidylate synthase (TS) expression. Among many other potential targets, histone deacetylase inhibitors (HDACi) modulate TS expression, potentially sensitizing to the cytotoxic action of anti-cancer drugs that target the folate pathway, such as pemetrexed. Since high levels of TS have been linked to clinical resistance to pemetrexed in NSCLC, herein we investigated the molecular and functional effects of combined pemetrexed and ITF2357, a pan-HDACi currently in clinical trials as an anti-cancer agent.ResultsIn NSCLC cell lines, HDAC inhibition by ITF2357 induced histone and tubulin acetylation and downregulated TS expression at the mRNA and protein level. In combination experiments in vitro ITF2357 and pemetrexed demonstrated sequence-dependent synergistic growth-inhibitory effects, with the sequence pemetrexed followed by ITF2357 inducing a strikingly synergistic reduction in cell viability and induction of both apoptosis and autophagy in all cell line models tested, encompassing both adenocarcinoma and squamous cell carcinoma. Conversely, simultaneous administration of both drugs achieved frankly antagonistic effects, while the sequence of ITF2357 followed by pemetrexed had additive to slightly synergistic growth-inhibitory effects only in certain cell lines. Similarly, highly synergistic growth inhibition was also observed in patient-derived lung cancer stem cells (LCSC) exposed to pemetrexed followed by ITF2357. In terms of molecular mechanisms of interaction, the synergistic growth-inhibitory effects observed were only partially related to TS modulation by ITF2357, as genetic silencing of TS expression potentiated growth inhibition by either pemetrexed or ITF2357 and, to a lesser extent, by their sequential combination. Genetic and pharmacological approaches provided an interesting link between the autophagic and apoptotic pathways, and showed that sequential pemetrexed/ITF2357 causes a toxic form of autophagy with consequent activation of a caspase-dependent apoptotic program. In vivo experiments in NSCLC xenografts confirmed that sequential pemetrexed/ITF2357 is feasible and results in increased inhibition of tumor growth and increased mice survival.ConclusionsOverall, these data provide a strong rationale for the clinical development of sequential schedules employing pemetrexed followed by HDACi in NSCLC.

Dataset Information

Selective cytotoxicity, inhibition of cell cycle progression, and induction of apoptosis in human breast cancer cells by sesquiterpenoids from Inula lineariifolia Turcz.

Publications

Selective cytotoxicity, inhibition of cell cycle progression, and induction of apoptosis in human breast cancer cells by sesquiterpenoids from Inula lineariifolia Turcz.

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