Targeted inhibition of telomerase activity combined with chemotherapy demonstrates synergy in eliminating ovarian cancer spheroid-forming cells

Meng, Erhong; Taylor, Brandon A.; Ray, Anasuya; Shevde, Lalita A.; Rocconi, Rodney P.

doi:10.1016/j.ygyno.2011.11.018

Cited by 26 publications

(24 citation statements)

References 16 publications

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“…Numerous treatments against cancers have been developed based on the expression discrepancy of hTERT between normal somatic cells and cancer cells [24]. Recently, it has been shown that targeted inhibition of telomerase activity with the BIBR1532 small molecule telomerase inhibitor combined with chemotherapy synergistically eliminated ovarian cancer spheroid-forming cells which indicates targeting telomerase activity may be a promising strategy against ovarian cancer [25]. In this study, we show for the first time that EGCG and SFN combination treatment can down-regulate hTERT expression as evidenced by both western blotting and telomerase activity assay.…”

Section: Discussionmentioning

confidence: 99%

Epigallocatechin gallate and sulforaphane combination treatment induce apoptosis in paclitaxel-resistant ovarian cancer cells through hTERT and Bcl-2 down-regulation

Chen

Landen

et al. 2013

Experimental Cell Research

101

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The cellular development of resistance to chemotherapy contributes to the high mortality noted in patients affected by ovarian cancer. Novel compounds that specifically target cellular drug resistance in ovarian cancer are therefore highly desired. Previous epidemiological studies indicate that consumption of green tea and cruciferous vegetables is inversely associated with occurrence of ovarian cancer. Therefore revealing the effects and mechanisms of major components of green tea (epigallocatechin gallate, EGCG) and cruciferous vegetables (sulforaphane, SFN) on ovarian cancer cells will provide necessary knowledge for developing potential novel treatments for the disease. In this study, EGCG or SFN was used to treat both paclitaxel-sensitive (SKOV3-ip1) and -resistant (SKOV3TR-ip2) ovarian cancer cell lines alone or in combination. We found that SFN inhibits cell viability of both ovarian cancer cell lines time- and dose-dependently and that EGCG potentiates the inhibiting effect of SFN on ovarian cancer cells. Cell cycle analysis indicates SFN can arrest ovarian cancer cells in G2/M phase, while EGCG and SFN co-treatment can arrest cells in both G2/M and S phase. Combined EGCG and SFN treatment increases apoptosis significantly in paclitaxel-resistant SKOV3TR-ip2 cells after 6 days of treatment, while reducing the expression of hTERT, the main regulatory subunit of telomerase. Western blotting also indicates that SFN can down-regulate Bcl-2 (a gene involved in anti-apoptosis) protein levels in both cell types. Cleaved poly(ADP-ribose) polymerase (PARP) becomes up-regulated by 6 days of treatment with SFN and this is more pronounced for combination treatment indicating induction of apoptosis. Furthermore, phosphorylated H2AX is up-regulated after 6 days of treatment with SFN alone, and EGCG can potentiate this effect, suggesting that DNA damage is a potential cellular mechanism contributing to the inhibiting effect of EGCG and SFN combination treatment. Taken together, these results indicate that EGCG and SFN combination treatment can induce apoptosis by down-regulating of hTERT and Bcl-2 and promote DNA damage response specifically in paclitaxel-resistant ovarian cancer cell lines and suggest the use of these compounds for overcoming paclitaxel resistance in ovarian cancer treatment.

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Section: Discussionmentioning

confidence: 99%

Epigallocatechin gallate and sulforaphane combination treatment induce apoptosis in paclitaxel-resistant ovarian cancer cells through hTERT and Bcl-2 down-regulation

Chen

Landen

et al. 2013

Experimental Cell Research

101

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“…Many researches suggested that telomerase activity closely correlated with level of hTERT transcription in most malignancy include breast cancer, malignant glioma, meningioma, cercival cancer. There have been reports which demonstrated that RNAi against telomerase reverse transcriptase (hTERT), could successfully inhibit telomerase activity in several cancer cell lines (Mo et al, 2003;Natarajan et al, 2004;Nakamura et al, 2005;Souza et al, 2006;Gandellini et al, 2007) and can enhance these radiosensitivity and chemosensitivity (Dong et al, 2009;George et al, 2010;Meng et al, 2012). However, the role of hTERC was not attracted enough attention as other target for telomerase activity regulation.…”

Section: Discussionmentioning

confidence: 99%

siRNA-mediated Inhibition of hTERC Enhances Radiosensitivity of Cervical Cancer

Chen¹,

Liu²

2012

Asian Pacific Journal of Cancer Prevention

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“…The transcriptional factor Slug is a well-documented EMT initiator in different cancers [7, 8], and hTERT induces OC cell invasion by upregulating Slug expression [5, 9]. The siRNA-mediated knockdown of hTERT and targeted inhibition of telomerase activity using the telomerase inhibitor BIBR1532 decreased hTERT expression and inhibited the proliferation and invasion of tumor cells [10, 11]. …”

Section: Introductionmentioning

confidence: 99%

MicroRNA-532 and microRNA-3064 inhibit cell proliferation and invasion by acting as direct regulators of human telomerase reverse transcriptase in ovarian cancer

Bai

Wang

et al. 2017

PLoS ONE

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Human telomerase reverse transcriptase (hTERT) plays a crucial role in ovarian cancer (OC) progression. However, the mechanisms underlying hTERT upregulation in OC, and the specific microRNAs (miRNAs) involved in the regulation of hTERT in OC cells, remains unclear. We performed a bioinformatics search to identify potential miRNAs that bind to the 3'-untranslated region (3'-UTR) region of the hTERT mRNA. We examined the expression levels of miR-532/miR-3064 in OC tissues and normal ovarian tissues, and analyzed the correlation between miRNA expression and OC patient outcomes. The impacts of miR-532/miR-3064 on hTERT expression were evaluated by western blot analysis and hTERT 3'-UTR reporter assays. We investigated the effects of miR-532/miR-3064 on proliferation and invasion in OC cells. We found that miR-532 and miR-3064 are down-regulated in OC specimens. We observed a significant association between reduced miR-532/miR-3064 expression and poorer survival of patients with OC. We confirmed that in OC cells, these two miRNAs downregulate hTERT levels by directly targeting its 3'-UTR region, and inhibited proliferation, EMT and invasion of OC cells. In addition, the overexpression of the hTERT cDNA lacking the 3'-UTR partially restored miR-532/miR-3064-inhibited OC cell proliferation and invasion. The silencing of hTERT by siRNA oligonucleotides abolished these malignant features, and phenocopied the effects of miR-532/miR-3064 overexpression. Furthermore, overexpression of miR-532/miR-3064 inhibits the growth of OC cells in vivo. Our findings demonstrate a miR-532/miR-3064-mediated mechanism responsible for hTERT upregulation in OC cells, and reveal a possibility of targeting miR-532/miR-3064 for future treatment of OC.

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Targeted inhibition of telomerase activity combined with chemotherapy demonstrates synergy in eliminating ovarian cancer spheroid-forming cells

Cited by 26 publications

References 16 publications

Epigallocatechin gallate and sulforaphane combination treatment induce apoptosis in paclitaxel-resistant ovarian cancer cells through hTERT and Bcl-2 down-regulation

Epigallocatechin gallate and sulforaphane combination treatment induce apoptosis in paclitaxel-resistant ovarian cancer cells through hTERT and Bcl-2 down-regulation

siRNA-mediated Inhibition of hTERC Enhances Radiosensitivity of Cervical Cancer

MicroRNA-532 and microRNA-3064 inhibit cell proliferation and invasion by acting as direct regulators of human telomerase reverse transcriptase in ovarian cancer

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