The apoptotic effects of the flavonoid N101-2 in human cervical cancer cells

Article · October 2011with20 Reads
DOI: 10.1016/j.tiv.2011.10.012 · Source: PubMed
Abstract
This study evaluated the anti-cancer effects of a naringenin derivative in human cervical cancer cells. In this study, a synthesized naringenin derivative, diethyl 5,7,4'-trihydroxy flavanone N-phenyl hydrazone (N101-2), inhibited cervical cancer cell growth, whereas naringenin itself exhibited no anti-cancer activity. N101-2 treatment inhibited cancer cell viability in a dose- and time-dependent manner through cell cycle arrest at sub-G1 phase, accompanied by an increase in apoptotic cell death. Expression of cyclins and ppRB was down-regulated, whereas that of CDK inhibitors and p53 increased upon N101-2 treatment. Meanwhile, we detected processing of caspases-8, -9, and -3, cleavage of PARP, as well as Bax up-regulation, which indicates activation of mitochondria-emanated intrinsic apoptosis signaling. Treatment with caspase-8 and -3 inhibitors also recovered cell cycling, and Fas/FasL expression increased in N101-2-treated cervical cancer cells, suggesting that Fas-mediated extrinsic apoptosis signaling was also activated. The tumor suppressor PTEN and its upstream regulator PPARγ were up-regulated with coincident inhibition of PI3K and phospho-Akt after N101-2 treatment. Taken together, we could conclude that N101-2 induces apoptosis by arresting the cell cycle at sub-G1 phase, activating mitochondria-emanated intrinsic and Fas-mediated extrinsic signaling pathways, and inhibiting the PI3K/AKT pathway in CaSki and SiHa human cervical cancer cells.
    • Nar potentiates the chemosensitivity of tested cancer cells in a drug-and cancertype dependent manner (Figures 6, 7,Table 2). These results are in line with findings in other malignancies[31,72,73]. Thus, Nar has the potential to be a useful adjunct to improve the effectiveness of chemotherapeutic agents in the treatment of human cancers.
    [Show abstract] [Hide abstract] ABSTRACT: Natural products with diverse bioactivities are becoming an important source of novel agents with medicinal potential. Cancer is a devastating disease that causes the death of millions of people each year. Thus, intense research has been conducted on several natural products to develop novel anticancer drugs. Chromatographic and spectral techniques were used for the isolation and identification of naringenin (Nar). MTT, flow cytometry, western blotting, Real Time PCR were used to test anticancer and chemosensitizing effects of Nar, cell cycle, apoptosis, and expression of cell cycle, apoptosis, pro-survival and anti-survival-related genes. In the present study, Thymus vulgaris ethanol extract was purified repeatedly to produce several compounds including the known flavanone, Nar which was identified using different spectral techniques. Nar was shown to inhibit both human colorectal and breast cancer cell growth in a dose- and time-dependent manner through cell cycle arrest at S- and G2/M-phases accompanied by an increase in apoptotic cell death. Additionally, Nar altered the expression of apoptosis and cell-cycle regulatory genes by down-regulating Cdk4, Cdk6, Cdk7, Bcl2, x-IAP and c-IAP-2 and up-regulating p18, p19, p21, caspases 3, 7, 8 and 9, Bak, AIF and Bax in both colorectal and breast cancer cells. Conversely, it diminished the expression levels of the cell survival factors PI3K, pAkt, pIκBα and NFκBp65. Moreover, Nar enhanced the sensitivity of colorectal and breast cancer cells to DNA-acting drugs. These findings provide evidence that Nar's pro-apoptotic and chemo-sensitizing effects are mediated by perturbation of cell cycle, upregulation of pro-apoptotic genes and down-regulation of anti-apoptotic genes and inhibition of pro-survival signaling pathways. In conclusion, Nar might be a promising candidate for chemoprevention and/or chemotherapy of human cancers. However, further studies exploring this therapeutic strategy are necessary.
    Full-text · Article · Dec 2015
    • Although the treatment of human cervical cancer cells (positive for HPV16 or HPV18) with widespread dietary flavanones including fruit flavonoids hesperetin, naringenin and naringin can lead to a dose-and timedependent inhibition of proliferation (seeTable 2), this activity reveals only at rather high concentrations (usually more than 100μM) and there are no cytotoxic effects on the cell viability at lower doses (Virgili et al., 2004;Kanno et al., 2005;Liu et al., 2011;Kim et al., 2012;Xie SR et al., 2012;Alshatwi et al., 2013;Ramesh and Alshatwi, 2013;Deng et al., 2014). This anticancer action occurs
    [Show abstract] [Hide abstract] ABSTRACT: Cervical cancer is the most common gynecologic malignancy worldwide and development of new therapeutic strategies and anticancer agents is an urgent priority. Plants have remained an important source in the search for novel cytotoxic compounds and several polyphenolic flavonoids possess antitumor properties. In this review article, data about potential anticarcinogenic activity of common natural flavonoids on various human cervical cancer cell lines are compiled and analyzed showing perspectives for the use of these secondary metabolites in the treatment of cervical carcinoma as well as in the development of novel chemotherapeutic drugs. Such anticancer effects of flavonoids seem to differentially depend on the cellular type and origin of cervical carcinoma creating possibilities for specific targeting in the future. Besides the cytotoxic activity per se, several flavonoids can also contribute to the increase in efficacy of conventional therapies rendering tumor cells more sensitive to standard chemotherapeutics and irradiation. Although the current knowledge is still rather scarce and further studies are certainly needed, it is clear that natural flavonoids may have a great potential to benefit cervical cancer patients.
    Full-text · Article · Oct 2014
    • Thereby, DHC and fisetin induced apoptosis, but not accelerated senescence in prostate cells (Haddad 2008). The study on diethyl 5,7,4 0 -trihydroxy flavanone N-phenyl hydrazone (N101-2), a synthesized naringenin derivative exhibited cervical cancer cell growth inhibition by arresting the cell cycle at sub-G1 phase, activating mitochondriaemanated intrinsic and Fas-mediated extrinsic signaling pathways, and inhibiting the PI3K/AKT pathway in CaSki and SiHa human cervical cancer cells (Kim et al. 2012).
    [Show abstract] [Hide abstract] ABSTRACT: Cancer is a major public health concern in both developed and developing countries. Several plant-derived anti-cancer agents including taxol, vinblastine, vincristine, the campothecin derivatives, topotecan, irinotecan and etoposide are in clinical use all over the world. Other promising anti-cancer agents include flavopiridol, roscovitine, combretastatin A-4, betulinic acid and silvestrol. From this list one can well imagine the predominance of polyphenols, flavonoids and their synthetic analogs in the treatment of ovarian, breast, cervical, pancreatic and prostate cancer. Flavonoids present in human diet comprise many polyphenolic secondary metabolites with broad-spectrum pharmacological activities including their potential role as anti-cancer agents. A positive correlation between flavonoids-rich diet (from vegetables and fruits) and lower risk of colon, prostate and breast cancers lead to a question that whether flavonoids mediate the protective effects as chemopreventive agents or can interact with different genes and proteins to play role in chemotherapy. The current review emphasizes onto the therapeutic potential of flavonoids and their synthetic analogs as anti-cancer agents by providing new insights into the factors, regulation and molecular mechanisms along with their significant protein interactions.
    Full-text · Article · Dec 2013
    • The results showed that FAFs inhibited the growth of those cancer cells in a concentration- and time-dependent manner. This was consistent with previous reports stating that flavonoids result in the inhibition of proliferation of human hepatocellular carcinoma cells in a dose- and time-dependent manner (17,18).
    [Show abstract] [Hide abstract] ABSTRACT: The flavonoids found in many foods may have a protective effect against human gastric cancer. However, little information is available concerning the effects of flavonoids on the SGC-7901 cell line. Therefore, we first evaluated the effects of purified Flos Albiziae flavonoids (FAFs) on the proliferation of the SGC-7901 human gastric cancer cell line and investigated its possible anti-proliferative mechanisms. When SGC-7901 cells were treated with FAFs for various time periods (12-72 h) and at various doses (0-32 μg/ml), cell growth decreased significantly in a time- and dose-dependent manner. Morphological observations with fluorescence microscopy and transmission electron microscopy (TEM) yielded clear evidence of cell shrinkage, formation of cytoplasmic filaments, condensation of nuclear chromatin, and cell apoptosis in the presence of FAFs. Treatment with FAFs changed the expression levels of Bcl-2, P65, Bax and caspase. The anti-apoptotic protein expression of Bcl-2 and p65 decreased gradually with the increase in FAF concentration, compared with control cells (P<0.05). FAFs contributed to the increase in Bax and caspase expression. The expression of pro-apoptotic proteins Bax and caspase were upregulated by FAFs compared with control cells (P<0.01). These results demonstrated that FAFs effectively induced apoptosis in the SGC-7901 cell line. This indicates that FAFs are likely to possess anticancer activity.
    Full-text · Article · Jan 2013
  • [Show abstract] [Hide abstract] ABSTRACT: Genistein is the most abundant isoflavone in soybeans. It has exhibited diverse biological activities, among these, its anticancer effects is most noteworthy. Through regulating critical cell cycle genes, genistein can inhibit cancer cell growth in vivo and in vitro. It has been reported that genistein can inhibit activation of NF-κB and Akt signaling pathways to induce cell apopt1osis, both pathways are well known for their function to maintain a balance between cell survival and apoptosis. In order to find out more outstanding anticancer isoflavone agents, against cancers extended synthesis of genistein derivatives has been carried out. Some of these synthetic compounds demonstrated higher anticancer activity with lower doses. Based on these results, genistein and its synthetic derivatives may be an emerging new type of anticancer agents.
    Article · Feb 2012
  • [Show abstract] [Hide abstract] ABSTRACT: Background: The globular heads of the human C1q receptor (gC1qR) are multi-compartmental and multi-functional cellular proteins. The list of biological responses mediated by the gC1qR includes growth perturbation and morphological abnormalities, along with the initiation of apoptosis. However, the effects of the gC1qR on the apoptosis of cervical squamous carcinoma cells (C33a and SiHa) have not been demonstrated. Methods: Here, human cervical tissues were examined for the expression of the gC1qR using real-time PCR and Western blot analysis. Apoptotic death of C33a and SiHa cells was assessed by flow cytometric analysis to detect the subG1 population. Viability, migration and proliferation of C33a and SiHa cells were detected via the water-soluble tetrazolium salt (WST-1) assay, the Transwell assay and the (3)H-thymidine incorporation into DNA assay ((3)H-TdR), respectively. Results: These data showed that expression of the gC1qR protein was significantly decreased in human cervical squamous cell carcinoma tissues relative to normal cervix tissues. C33a and SiHa cells transfected with a GFP-gC1qR vector resulted in the up-regulation of cellular apoptosis and an apparent increase in the expression of the p38 mitogen-activated protein kinase (p38 MAPK). Further, the changes in C33a and SiHa cells viability, migration and proliferation observed upon overexpression of gC1qR could be abrogated using the p38 MAPK inhibitor SB202190. Conclusion: These data indicate that gC1qR inhibits viability, migration and proliferation of cervical squamous cells carcinoma via the p38 MAPK signalling pathway.
    Article · Oct 2012
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