Thymoquinone up-regulates PTEN expression and induces apoptosis in doxorubicin-resistant human breast cancer cells

Abstract

The use of innocuous naturally occurring compounds to overcome drug resistance and cancer recalcitrance is now in the forefront of cancer research. Thymoquinone (TQ) is a bioactive constituent of the volatile oil derived from seeds of Nigella sativa Linn. TQ has shown promising anti-carcinogenic and anti-tumor activities through different mechanisms. However, the effect of TQ on cell signaling and survival pathways in resistant cancer cells has not been fully delineated. Here, we report that TQ greatly inhibits doxorubicin-resistant human breast cancer MCF-7/DOX cell proliferation. TQ treatment increased cellular levels of PTEN proteins, resulting in a substantial decrease of phosphorylated Akt, a known regulator of cell survival. The PTEN expression was accompanied with elevation of PTEN mRNA. TQ arrested MCF-7/DOX cells at G2/M phase and increased cellular levels of p53 and p21 proteins. Flow cytometric analysis and agarose gel electrophoresis revealed a significant increase in Sub-G1 cell population and appearance of DNA ladders following TQ treatment, indicating cellular apoptosis. TQ-induced apoptosis was associated with disrupted mitochondrial membrane potential and activation of caspases and PARP cleavage in MCF-7/DOX cells. Moreover, TQ treatment increased Bax/Bcl2 ratio via up-regulating Bax and down-regulating Bcl2 proteins. More importantly, PTEN silencing by target specific siRNA enabled the suppression of TQ-induced apoptosis resulting in increased cell survival. Our results reveal that up-regulation of the key upstream signaling factor, PTEN, in MCF-7/DOX cells inhibited Akt phosphorylation, which ultimately causes increase in their regulatory p53 levels affecting the induction of G2/M cell cycle arrest and apoptosis. Overall results provide mechanistic insights for understanding the molecular basis and utility of the anti-tumor activity of TQ.

Thymoquinone Inhibits Autophagy and Induces Cathepsin-Mediated, Caspase-Independent Cell Death in Glioblastoma Cells

“…Its purported health benefits include anti-inflammatory, anti-oxidant and anti-hypertensive actions. We have shown that TQ induces apoptosis in HL-60 leukemia cells and MCF-7/DOX doxorubicin-resistant breast cancer cells [22], [23]. Additionally, a number of other studies have reported that the anti-tumor functions of TQ are specific for cancer cells [24], [25].…”

Curcumin Enhances the Efficacy of Chemotherapy by Tailoring p65NFκB-p300 Cross-talk in Favor of p53-p300 in Breast Cancer

“…Unfortunately, many breast tumor cells are inherently resistant to doxorubicin or can acquire chemoresistance shortly after therapy, which inevitably leads to treatment failure and relapse of the disease (2,3). An accumulating body of evidence suggests that constitutive activation of the NFB pathway can contribute to cancer development, progression, and resistance to cancer therapy (4,5), whereas activation of this pathway by doxorubicin can also render tumor cells more resistant to chemotherapy (6).…”

“…Doxorubicin, an anthracycline antibiotic, is one of the commonly prescribed chemotherapeutic agents against a wide-spectrum of cancers including breast cancer (2). However, the clinical efficacy and usefulness of doxorubicin-based treatment regimens is still limited because of dose-limiting toxicity and induction of drug resistance (3). Therefore, there is an urgent need to develop new sensitizing agents that enhance the efficacy of doxorubicin and circumvent chemoresistance.…”

Effects of Polyphenol-Rich Foods on Human Health

“…Citrus fruit polysaccharides in vitro inhibiting angiogenesis and cell migration [113] Nutrients 2017, 9, 728 [141] jamun fruit NA in vitro inhibiting proliferation and inducing apoptosis [142] cranberry NA in vitro inducing apoptosis and G1 phase arrest [143] Nutrients 2017, 9, 728 [189][190][191] in vitro -inducing cell cycle arrest -lowering the invasive and metastatic potential -stimulating the expression and secretion of IFNγ [192][193][194][195][196][197] red beetroot betanin in vitro showing a dose-dependent cytotoxic effect [198] Nutrients 2017, 9, 728 inhibiting invasion by reducing MMP-9 expression via blockade of NF-κB activation [204] inhibiting invasion by suppressing invadopodium formation and MMP activity [205] inhibiting growth and sustainability of spheroid generated from adherent breast cancer cells [206] ginger 6-dehydrogingerdione in vitro inducing apoptosis and cell cycle arrest in G 2 /M phase [207] garlic diallyl disulfide in vitro inducing apoptosis though: -inhibition of histone deacetylation -inhibition of ERK and the activation of the SAPK/JNK and p38 pathways [216,217] in vitro and in vivo inhibit proliferation and metastasis via: -suppression of the SRC/Ras/ERK pathway -inactivation of the β-catenin signaling pathway [218,219] garlic diallyl trisulfide in vitro and in vivo inducing apoptosis though: -overproduction of ROS and subsequent activation of JNK and AP-1 -upregulating FAS, Bax and p53, and down-regulating Akt and Bcl-2 [220,221] in vitro -inhibiting migration and invasion; -inhibiting ER-α -decreasing protein level of FoxQ1 [213,222,223] garlic S-allyl mercaptocysteine in vitro inducing mitochondrial apoptosis and cell cycle arrest [214] garlic allicin in vitro inhibiting invasion and metastasis [215] black cumin extracts in vitro inducing apoptosis and inhibiting metastasis [224,225] black cumin thymoquinone in vitro and in vivo inducing apoptosis through: -inhibiting Akt phosphorylation -inducing p38 phosphorylation via ROS generation …”