Etoposide resistance in MCF-7 breast cancer cell line is marked by multiple mechanisms

Alpsoy, Aktan; Yasa, Seda; Gündüz, Ufuk

doi:10.1016/j.biopha.2013.09.007

Cited by 34 publications

(25 citation statements)

References 16 publications

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“…It was previously noted that the V79 cells are generally more sensitive toward both DOX and etoposide than the MCF7 cells. 63 That was shown also here with both etoposide and ANS–etoposide. However, MGST1 over-expression seemed to promote a weak ANS–etoposide induced toxicity compared to control cells and in relation to the parental etoposide (Figure 7B).…”

Section: Resultssupporting

confidence: 80%

Chemical Reactivity Window Determines Prodrug Efficiency toward Glutathione Transferase Overexpressing Cancer Cells

et al. 2016

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Glutathione transferases (GSTs) are often overexpressed in tumors and frequently correlated to bad prognosis and resistance against a number of different anticancer drugs. To selectively target these cells and to overcome this resistance we previously have developed prodrugs that are derivatives of existing anticancer drugs (e.g., doxorubicin) incorporating a sulfonamide moiety. When cleaved by GSTs, the prodrug releases the cytostatic moiety predominantly in GST overexpressing cells, thus sparing normal cells with moderate enzyme levels. By modifying the sulfonamide it is possible to control the rate of drug release and specifically target different GSTs. Here we show that the newly synthesized compounds, 4-acetyl-2-nitro-benzenesulfonyl etoposide (ANS–etoposide) and 4-acetyl-2-nitro-benzenesulfonyl doxorubicin (ANS–DOX), function as prodrugs for GSTA1 and MGST1 overexpressing cell lines. ANS–DOX, in particular, showed a desirable cytotoxic profile by inducing toxicity and DNA damage in a GST-dependent manner compared to control cells. Its moderate conversion of 500 nmol/min/mg, as catalyzed by GSTA1, seems hereby essential since the more reactive 2,4-dinitrobenzenesulfonyl doxorubicin (DNS–DOX) (14000 nmol/min/mg) did not display a preference for GSTA1 overexpressing cells. DNS–DOX, however, effectively killed GSTP1 (20 nmol/min/mg) and MGST1 (450 nmol/min/mg) overexpressing cells as did the less reactive 4-mononitrobenzenesulfonyl doxorubicin (MNS–DOX) in a MGST1-dependent manner (1.5 nmol/min/mg) as shown previously. Furthermore, we show that the mechanism of these prodrugs involves a reduction in GSH levels as well as inhibition of the redox regulatory enzyme thioredoxin reductase 1 (TrxR1) by virtue of their electrophilic sulfonamide moiety. TrxR1 is upregulated in many tumors and associated with resistance to chemotherapy and poor patient prognosis. Additionally, the prodrugs potentially acted as a general shuttle system for DOX, by overcoming resistance mechanisms in cells. Here we propose that GST-dependent prodrugs require a conversion rate “window” in order to selectively target GST overexpressing cells, while limiting their effects on normal cells. Prodrugs are furthermore a suitable system to specifically target GSTs and to overcome various drug resistance mechanisms that apply to the parental drug.

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Section: Resultssupporting

confidence: 80%

Chemical Reactivity Window Determines Prodrug Efficiency toward Glutathione Transferase Overexpressing Cancer Cells

et al. 2016

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“…Resistance against chemotherapy and radiation therapy in breast cancer has been attributed to the presence of CSC population in the tumor which later proliferates and results in relapse (Smith et al, 2007;Kwok et al, 2010;Nakshatri, 2010;Lai et al, 2011;Printz, 2012;Alpsoy et al, 2014). To examine whether PG sensitizes BCSCs to chemotherapy and radiation therapy, sphere-cultured breast cancer cells were treated with PG or control DMSO prior to treatment with cisplatin, etoposide, taxol or ionizing radiation (10 Gy).…”

Section: Pg Sensitizes Breast Cancer Cells To Anticancer Treatmentmentioning

confidence: 99%

Novel anticancer activity of phloroglucinol against breast cancer stem-like cells

Kim

Uddin

Hyun

et al. 2015

Toxicology and Applied Pharmacology

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“…22 It is linked to DNA-damage signaling pathway 23,24 and directly regulates progestin-mediated signaling pathway 21 and mitogen-activated protein kinase pathway. 25 A more direct role for EDD1 in carcinogenesis is suggested by its overexpression in several cancers, including ovarian and breast cancer, 26,27 whereas truncating mutations have been detected in gastric and colon cancers. 28 Information regarding the functional role of TIP60 in viralmediated cancers has been very limited.…”

Section: Introductionmentioning

confidence: 98%

E3 ligase EDD1/UBR5 is utilized by the HPV E6 oncogene to destabilize tumor suppressor TIP60

et al. 2015

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Tat-interacting protein of 60 kDa (TIP60) is an essential lysine acetyltransferase implicated in transcription, DNA damage response and apoptosis. TIP60 protein expression is reduced in cancers. In cervical cancers, human papillomavirus (HPV) E6 oncogene targets cellular p53, Bak and some of the PDZ domain-containing proteins for proteasome-mediated degradation through E6AP ligase. Recently, E6 oncogene from high-risk and low-risk categories was also shown to target TIP60. However, the molecular mechanisms and whether destabilization of TIP60 contributes to HPV E6-mediated transformation remain unanswered. Our proteomic analyses revealed EDD1 (E3 identified by differential display), an E3 ligase generally overexpressed in cancers as a novel interacting partner of TIP60. By investigating protein turnover and ubiquitination assays, we show that EDD1 negatively regulates TIP60's stability through the proteasome pathway. Strikingly, HPV E6 uses this function of EDD1 to destabilize TIP60. Colony-formation assays and soft agar assays show that gain of function of TIP60 or depletion of EDD1 in HPV-positive cervical cancer cells significantly inhibits cell growth in vitro. This phenotype is strongly supported by the in-vivo studies where re-activation of TIP60 in cervical cancer cells dramatically reduces tumor formation. In summary, we have discovered a novel ligase through which E6 destabilizes TIP60. Currently, in the absence of an effective therapeutic vaccine for malignant cervical cancers, cervical cancer still remains to be a major disease burden. Hence, our studies implying a distinct tumor suppressor role for TIP60 in cervical cancers show that reactivation of TIP60 could be of therapeutic value.

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Etoposide resistance in MCF-7 breast cancer cell line is marked by multiple mechanisms

Cited by 34 publications

References 16 publications

Chemical Reactivity Window Determines Prodrug Efficiency toward Glutathione Transferase Overexpressing Cancer Cells

Chemical Reactivity Window Determines Prodrug Efficiency toward Glutathione Transferase Overexpressing Cancer Cells

Novel anticancer activity of phloroglucinol against breast cancer stem-like cells

E3 ligase EDD1/UBR5 is utilized by the HPV E6 oncogene to destabilize tumor suppressor TIP60

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