Synthesis of coumaperine derivatives: Their NF-κB inhibitory effect, inhibition of cell migration and their cytotoxic activity

Nandakumar, Natarajan; Sundararaman, Muthuraman; Gopinath, Pushparathinam; Nithya, P.; Gopas, Jacob; Kumar, Rajendran Saravana

doi:10.1016/j.ejmech.2016.10.047

Cited by 15 publications

(14 citation statements)

References 32 publications

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“…As a critical transcription factor, constitutive NF-κB activity was observed in a larger number of human cancers and promoted growth and progression, including that in prostate cancer [25,26,46]. In addition, HOTAIR expression was associated with induced proliferation and aggressive behavior of cancer cells, resulting in poor prognosis [19][20][21].…”

Section: Discussionmentioning

confidence: 99%

“…Given the tumor promoter roles of NF-κB [25,26] and LncRNA HOTAIR [20,21], we evaluated the effects of PPI with or without enzalutamide. We showed that PPI decreased NF-κB subunit p65 protein expression ( Fig.…”

Section: Ppi Decreased the Protein Expression Levels Of P65 And Lncrnmentioning

confidence: 99%

“…NF-κB is activated by various extracellular signals and regulates the expression of different genes [23,24]. Constitutive NF-κB activity was observed in a large number of human cancers and shown to play an important role in the process from inflammation to carcinogenesis; constitutive NF-κB activation is a targeted intervention in various malignancies, including prostate cancer [25,26]. Limited studies have reported the potential role of NF-κB in mediating the therapeutic effects of PPI [27].…”

Section: Introductionmentioning

confidence: 99%

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Crosstalk of NF-κB/P65 and LncRNA HOTAIR-Mediated Repression of MUC1 Expression Contribute to Synergistic Inhibition of Castration-Resistant Prostate Cancer by Polyphyllin 1–Enzalutamide Combination Treatment

Xiang

Zou

et al. 2018

Cell Physiol Biochem

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Background/Aims: Polyphyllin I (PPI), one of the steroidal saponins in Paris polyphylla, reportedly exhibits antitumor effects. However, the detailed mechanism underlying PPI, particularly in enhancing the effect of the androgen receptor inhibitor enzalutamide in controlling castration-resistant prostate cancer (CRPC) has not been explored. Methods: Cell viability and cell cycle distribution were measured using 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) and flow cytometry assays, respectively. Long non-coding RNA (lncRNA) HOX transcript antisense RNA (HOTAIR) expression was measured by quantitative real time-PCR (qRT-PCR). Western blot analysis was performed to determine the protein expression levels of MUC1, p65, and p50. Silencing of HOTAIR was evaluated using the siRNA procedure. The promoter activity of the MUC1 gene was determined using Secrete-Pair Dual Luminescence Assay Kit. Exogenous expression of HOTAIR, p65, and MUC1 was conducted by transient transfection assay. A xenograft tumor model in nude mice was used to further evaluate the effect of the combination of PPI and enzalutamide in vivo. Results: We showed that PPI significantly inhibited growth and induced cell cycle arrest in CRPC cells. PPI also decreased p65 and MUC1 protein expression and reduced HOTAIR expression. Exogenously expressed p65 resisted the PPI-inhibited expression of HOTAIR, whereas silenced HOTAIR reduced MUC1 protein but exerted no effect on the expression of p65 and p50 proteins. Conversely, exogenously expressed HOTAIR resisted the PPI-inhibited MUC1 protein expression, and excessive expression of MUC1 antagonized the PPI-inhibited cell growth. Notably, PPI combined with enzalutamide exerted a synergistic effect. Consistent with this finding, PPI inhibited tumor growth, HOTAIR expression, as well as p65 and MUC1 protein expressions in vivo. Conclusions: Our results indicate that PPI inhibits the growth of CRPC cells by inhibiting p65 protein and concomitantly reducing HOTAIR expression, thereby suppressing MUC1 gene expression. The novel regulatory interaction of p65 and HOTAIR converge in the inhibition of MUC1 expression and overall PPI response. The combination of PPI and enzalutamide exhibits synergy. This study reveals a novel mechanism underlying the synergistic inhibitory effect of PPI and enzalutamide on the growth of CRPC cells.

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Section: Discussionmentioning

confidence: 99%

Section: Ppi Decreased the Protein Expression Levels Of P65 And Lncrnmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Crosstalk of NF-κB/P65 and LncRNA HOTAIR-Mediated Repression of MUC1 Expression Contribute to Synergistic Inhibition of Castration-Resistant Prostate Cancer by Polyphyllin 1–Enzalutamide Combination Treatment

Xiang

Zou

et al. 2018

Cell Physiol Biochem

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“…Therefore, these results indicate that 19 exhibits signi cant inhibitory effects on the migration of MDA-MB-468 and PANC-1 cells with a more pronounced effect on the former. The migration ability of cancer cells is a crucial factor in invasion and metastasis [15], therefore, these results and those of the clonogenic assay, re ect the potential of 19 to reduce or inhibit cancer cell survival, invasion and metastasis in patients. The induction of G2/M-phase cell-cycle arrest by certain agents often indicates that they also cause DNA damage [16].…”

Section: Resultsmentioning

confidence: 99%

Novel semi-synthetic Cu (II)-cardamonin complex exerts potent anticancer activity against triple negative breast and pancreatic cancer cells via inhibition of the Akt signaling pathway

Hossan

Break

Bradshaw

et al. 2021

Preprint

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Triple negative breast cancer (TNBC) and pancreatic cancer are two of the most aggressive types of cancer that lack effective treatments. We have previously reported the semi-synthesis of a novel Cu (II)-cardamonin complex (19) that demonstrated potent anti-tumour activity. In this study, we further investigated the bioactivity and mode of action of 19 against MDA-MB-468 and PANC-1 cancer cells in an attempt to discover an effective anticancer agent for TNBC and pancreatic cancer, respectively. Results revealed that 19 abolished formation of MDA-MB-468 and PANC-1 colonies, exerted growth inhibitory activity and inhibited the migration of cancer cells. Further mechanistic studies showed that it induced DNA damage resulting in G2/M-phase arrest and microtubule network disruption. Moreover, there was an increase in ROS production which may have contributed to the observed induction of apoptosis, corroborated by activation of caspase-3/7, cleavage of PARP and downregulation of Mcl-1. Complex 19 also decreased the expression levels of p-Akt and p-4EBP1 in both cell lines, which indicates that the compound exerted its activity, at least in part, via inhibition of the Akt signaling pathway. Furthermore, it decreased the expression of c-Myc in PANC-1 cells only which suggests that it may exert its bioactivity via multiple mechanisms of action pertinent to tumourigenesis. These results demonstrate the potential of 19 as a promising therapeutic agent for TNBC and pancreatic cancer.

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“…Therefore, these results indicate that 19 exhibits significant inhibitory effects on the migration of MDA-MB-468 and PANC-1 cells with a more pronounced effect on the former. The migration ability of cancer cells is a crucial factor in invasion and metastasis [14]; therefore, these results and those of the clonogenic assay reflect the potential of 19 to reduce or inhibit cancer cell survival, invasion, and metastasis in patients. A,B) The migration assay was conducted by forming a "wound" across a layer of cells followed by treatment with either solvent control or 19 at concentrations of 1 × GI 50 and 2 × GI 50 .…”

Section: Compound 19 Inhibited the Growth And Migration Of Mda-mb-468 And Panc-1 Cancer Cellsmentioning

confidence: 92%

Novel Semi-Synthetic Cu (II)–Cardamonin Complex Exerts Potent Anticancer Activity against Triple-Negative Breast and Pancreatic Cancer Cells via Inhibition of the Akt Signaling Pathway

et al. 2021

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Cardamonin is a polyphenolic natural product that has been shown to possess cytotoxic activity against a variety of cancer cell lines. We previously reported the semi-synthesis of a novel Cu (II)–cardamonin complex (19) that demonstrated potent antitumour activity. In this study, we further investigated the bioactivity of 19 against MDA-MB-468 and PANC-1 cancer cells in an attempt to discover an effective treatment for triple-negative breast cancer (TNBC) and pancreatic cancer, respectively. Results revealed that 19 abolished the formation of MDA-MB-468 and PANC-1 colonies, exerted growth-inhibitory activity, and inhibited cancer cell migration. Further mechanistic studies showed that 19 induced DNA damage resulting in gap 2 (G2)/mitosis (M) phase arrest and microtubule network disruption. Moreover, 19 generated reactive oxygen species (ROS) that may contribute to induction of apoptosis, corroborated by activation of caspase-3/7, PARP cleavage, and downregulation of Mcl-1. Complex 19 also decreased the expression levels of p-Akt and p-4EBP1, which indicates that the compound exerts its activity, at least in part, via inhibition of Akt signalling. Furthermore, 19 decreased the expression of c-Myc in PANC-1 cells only, which suggests that it may exert its bioactivity via multiple mechanisms of action. These results demonstrate the potential of 19 as a therapeutic agent for TNBC and pancreatic cancer.

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Synthesis of coumaperine derivatives: Their NF-κB inhibitory effect, inhibition of cell migration and their cytotoxic activity

Cited by 15 publications

References 32 publications

Crosstalk of NF-κB/P65 and LncRNA HOTAIR-Mediated Repression of MUC1 Expression Contribute to Synergistic Inhibition of Castration-Resistant Prostate Cancer by Polyphyllin 1–Enzalutamide Combination Treatment

Crosstalk of NF-κB/P65 and LncRNA HOTAIR-Mediated Repression of MUC1 Expression Contribute to Synergistic Inhibition of Castration-Resistant Prostate Cancer by Polyphyllin 1–Enzalutamide Combination Treatment

Novel semi-synthetic Cu (II)-cardamonin complex exerts potent anticancer activity against triple negative breast and pancreatic cancer cells via inhibition of the Akt signaling pathway

Novel Semi-Synthetic Cu (II)–Cardamonin Complex Exerts Potent Anticancer Activity against Triple-Negative Breast and Pancreatic Cancer Cells via Inhibition of the Akt Signaling Pathway

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