Antiproliferative Effects of Cucurbitacin B in Breast Cancer Cells: Down-Regulation of the c-Myc/hTERT/Telomerase Pathway and Obstruction of the Cell Cycle

Duangmano, Suwit; Dakeng, Sumana; Jiratchariyakul, Weena; Suksamrarn, Apichart; Smith, Duncan R.; Patmasiriwat, Pimpicha

doi:10.3390/ijms11125323

Cited by 56 publications

(46 citation statements)

References 37 publications

(39 reference statements)

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“…Furthermore, it enhances the anticancer effects of clinical chemotherapeutic drugs: cisplatin, gemcitabine, methotrexate, docetaxel, and gemcitabine [9][10][11][12]. Documented results also demonstrate that Cuc B potently inhibits the proliferation of breast cancer cell lines both in vitro and in vivo [13][14][15][16][17]. Cuc B suppressed breast cancer cell growth by HER2/integrin signaling, which further led to inhibiting integrin-mediated cell survival through ILK1 and paxillin [14], by disruption of microtubule polymerization and disturbance of nucleophosmin/ B23 translocation [15], and by inhibiting Wnt signaling [18].…”

Section: Introductionmentioning

confidence: 80%

Cucurbitacin B induces DNA damage and autophagy mediated by reactive oxygen species (ROS) in MCF-7 breast cancer cells

et al. 2015

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Cucurbitacin B (Cuc B), a natural compound extracted from cucurbitaceous plants, demonstrated potent anticancer activities, while the underlying mechanisms remain unclear. We investigated the anticancer effect of Cuc B on MCF-7 breast cancer cells. Cuc B drastically decreased cell viability in a concentration-dependent manner. Cuc B treatment caused DNA damage, as shown by long tails in the comet assay and increased γH2AX protein expression. Immunofluorescence staining showed that Cuc B treatment induced nuclear γH2AX foci. Cuc B activated DNA damage pathways by phosphorylation of ATM/ATR [two large phosphatidylinositol-3-kinase-like kinase family (PIKKs) members]. Furthermore, it also induced autophagy, as evidenced by monodansylcadaverine (MDC) staining and autophagic protein expression. In addition, Cuc B treatment led to increased reactive oxygen species (ROS) formation, which was inhibited by N-acetyl-L-cysteine (NAC) pretreatment. NAC pretreatment inhibited Cuc-B-induced DNA damage and autophagy. Taken together, these results suggest that ROS-mediated Cuc-B-induced DNA damage and autophagy in MCF-7 cells, which provides new insights into the anticancer molecular mechanism of Cuc B.

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Section: Introductionmentioning

confidence: 80%

Cucurbitacin B induces DNA damage and autophagy mediated by reactive oxygen species (ROS) in MCF-7 breast cancer cells

et al. 2015

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“…1A - D). Previous studies reported significantly high IC50 of CuB in normal mammary epithelial cell lines as compared to SKBR3 breast cancer cells [36]. To confirm the non-toxic effects of CuB, we evaluated its toxicity in a normal human melanocyte epithelial (PIG1) cells.…”

Section: Resultsmentioning

confidence: 99%

Inhibition of HER2-integrin signaling by Cucurbitacin B leads to in vitro and in vivo breast tumor growth suppression

Gupta

Srivastava

2014

Oncotarget

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HER2, an oncogenic receptor is overexpressed in about 25-30% of breast cancer patients. HER2 has been shown to play role in tumor promotion by having cross-talk with multiple oncogenic pathways in cancer cells. Our results show that Cucurbitacin B (CuB), a triterpenoid steroidal compound inhibited the growth of various breast cancer cells with an IC50 ranging from 18-50nM after 48 and 72 h of treatment. Our study also revealed the significant inhibitory effects of CuB on HER2 and integrin signaling in breast cancer. Notably, CuB inhibited ITGA6 and ITGB4 (integrin α6 & integrin β4), which are overexpressed in breast cancer. Furthermore, CuB also induced the expression of major ITGB1and ITGB3, which are known to cause integrin-mediated cell death. In addition, we observed that TGFβ treatment resulted in the increased association of HER2 with ITGA6 and this association was inhibited by CuB treatment. Efficacy of CuB was tested in vivo using two different orthotopic models of breast cancer. MDA-MB-231 and 4T-1 cells were injected orthotopically in the mammary fat pad of female athymic nude mice or BALB/c mice respectively. Our results showed that CuB administration inhibited MDA-MB-231 orthotopic tumors by 55%, and 4T-1 tumors by 40%. The 4T-1 cells represent stage IV breast cancer and form very aggressive tumors. CuB mediated breast tumor growth suppression was associated with the inhibition of HER2/integrin signaling. Our results suggest novel targets of CuB in breast cancer in vitro and in vivo.

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“…As found in the other cucurbitacins, cucurbitacin B has been reported as the antiproliferative agent of breast cancer cells in vitro and in vivo [15] and can induce apoptosis in Bcap37 breast cancer cells [16]. Our previous work revealed that cucurbitacin B inhibits growth and telomerase activity in breast cancer cell lines (T47D, SKBR-3, and MCF-7) and the inhibitory effect was obviously seen in the estrogen receptor (ER)-negative breast cancer cells SKBR-3 [17]. It also inhibits hTERT and c-Myc protein expression.…”

Section: Introductionmentioning

confidence: 82%

The Effectiveness of Cucurbitacin B in BRCA1 Defective Breast Cancer Cells

et al. 2013

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Cucurbitacin B (CuB) is one of the potential agents for long term anticancer chemoprevention. Cumulative evidences has shown that cucurbitacin B provides potent cellular biological activities such as hepatoprotective, anti-inflammatory and antimicrobial effects, but the precise mechanism of this agent is not clearly understood. We examine the biological effects on cancer cells of cucurbitacin B extracted from a Thai herb, Trichosanthes cucumerina L. The wild type (wt) BRCA1, mutant BRCA1, BRCA1 knocked-down and BRCA1 overexpressed breast cancer cells were treated with the cucurbitacin B and determined for the inhibitory effects on the cell proliferation, migration, invasion, anchorage-independent growth. The gene expressions in the treated cells were analyzed for p21/Waf1, p27Kip1 and survivin. Our previous study revealed that loss of BRCA1 expression leads to an increase in survivin expression, which is responsible for a reduction in sensitivity to paclitaxel. In this work, we showed that cucurbitacin B obviously inhibited knocked-down and mutant BRCA1 breast cancer cells rather than the wild type BRCA1 breast cancer cells in regards to the cellular proliferation, migration, invasion and anchorage-independent growth. Furthermore, forcing the cells to overexpress wild type BRCA1 significantly reduced effectiveness of cucurbitacin B on growth inhibition of the endogenous mutant BRCA1 cells. Interestingly, cucurbitacin B promotes the expression of p21/Waf1 and p27Kip1 but inhibit the expression of survivin. We suggest that survivin could be an important target of cucurbitacin B in BRCA1 defective breast cancer cells.

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Antiproliferative Effects of Cucurbitacin B in Breast Cancer Cells: Down-Regulation of the c-Myc/hTERT/Telomerase Pathway and Obstruction of the Cell Cycle

Cited by 56 publications

References 37 publications

Cucurbitacin B induces DNA damage and autophagy mediated by reactive oxygen species (ROS) in MCF-7 breast cancer cells

Cucurbitacin B induces DNA damage and autophagy mediated by reactive oxygen species (ROS) in MCF-7 breast cancer cells

Inhibition of HER2-integrin signaling by Cucurbitacin B leads to in vitro and in vivo breast tumor growth suppression

The Effectiveness of Cucurbitacin B in BRCA1 Defective Breast Cancer Cells

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