β-lapachone suppresses the proliferation of human malignant melanoma cells by targeting specificity protein 1

Bang, Woong; Jeon, Young‐Joo; Cho, Jin Hyoung; Lee, Ra Ham; Park, Seon‐Min; Shin, Jae-Cheon; Choi, Nak Hwan; Choi, Yung Hyun; Cho, Jung-Jae; Seo, Jae-Min; Lee, Seung-Yeop; Shim, Jung‐Hyun; Chae, Jung‐Il

doi:10.3892/or.2015.4439

Cited by 20 publications

(15 citation statements)

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“…It ranks as the fifth most common cancer for male and the seventh most common malignancy in female (2,3). In recent years, a large number of studies have focused on the pathogenesis of MM, and deregulation of oncogenes and tumor suppressors have been reported to play key roles in the development and progression of MM (4,5). However, the detailed molecular mechanism underlying MM still remains largely unclear.…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-18b inhibits the growth of malignant melanoma via inhibition of HIF-1α-mediated glycolysis

et al. 2016

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Abstract. MicroRNAs (miRs) have been demonstrated to play critical roles in the development and progression of malignant melanoma (MM). However, the exact role and underlying mechanism of miR-18b in MM growth remains unclear. In the present study, real-time PCR data indicated that miR-18b was significantly downregulated in MM tissues compared to their matched adjacent non-tumor tissues. Low miR-18b expression was significantly associated with the tumor thickness and stage, although no significant association was observed between the miR-18b expression and the age, gender, or lymph node metastasis. Besides, miR-18b was also significantly downregulated in MM B16 and A375 cells compared to normal skin HACAT cells. Ectopic expression of miR-18b decreased the proliferation of A375 and B16 cells, while induced a remarkable cell cycle arrest at G1 stage. Besides, miR-18b overexpression also inhibited the glycolysis in A375 and B16 cells. HIF-1α, a key regulator in glycolysis, was then identified as a target gene of miR-18b, and its expression was negatively mediated by miR-18b in A375 and B16 cells. Overexpression of HIF-1α rescued the suppressive effect of miR-18b on MM cell proliferation and glycolysis. In vivo study further showed that overexpression of miR-18b inhibited the MM growth as well as the tumor-related death, accompanied with HIF-1α downregulation. Taken together, the present study suggests that miR-18b inhibits the growth of MM cells in vitro and in vivo through directly targeting HIF-1α.

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Section: Introductionmentioning

confidence: 99%

MicroRNA-18b inhibits the growth of malignant melanoma via inhibition of HIF-1α-mediated glycolysis

et al. 2016

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“…The present study focused on β-lap, a natural quinone derived from the bark of the Lapacho tree (12,13). Previous studies have revealed that β-lap acts as a potent anti-proliferative agent, inhibiting topoisomerase I/II (26,32,33), specificity protein 1 (26) and the cell cycle (34). It has also been shown that repetitive oxidation-reduction of β-lap by NQO1 generates ROS in tumor cells (14), thus contributing to cytotoxicity in malignancies, including pancreatic cancer (35,36).…”

Section: Discussionmentioning

confidence: 99%

“…The viabilities of the remaining six cell lines were also tested and the IC 50 values are presented in Table I. These corresponded to the values that had been reported previously for SK-MEL-28 and another cell line, G361 (26). The association between the basal expression levels of NQO1 and the IC 50 values of β-lap in eight melanoma cell lines were then compared.…”

Section: Effect Of β-Lap On Melanoma Cell Linesmentioning

confidence: 99%

Carnosic acid, an inducer of NAD(P)H quinone oxidoreductase 1, enhances the cytotoxicity of β‑lapachone in melanoma cell lines

et al. 2017

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Abstract. NAD(P)H quinone oxidoreductase 1 (NQO1)-dependent antitumor drugs such as β-lapachone (β-lap) are attractive candidates for cancer chemotherapy because several tumors exhibit higher expression of NQO1 than adjacent tissues. Although the association between NQO1 and β-lap has been elucidated, the effects of a NQO1-inducer and β-lap used in combination remain to be clarified. It has previously been reported that melanoma cell lines have detectable levels of NQO1 expression and are sensitive to NQO1-dependent drugs such as 17-allylamino-17-demethoxygeldanamycin. The present study was conducted to investigate the involvement of NQO1 in β-lap-mediated toxicity and the utility of combination treatment with a NQO1-inducer and β-lap in malignant melanoma cell lines. Decreased expression or inhibition of NQO1 caused these cell lines to become less sensitive to β-lap, indicating a requirement of NQO1 activity for β-lap-mediated toxicity. Of note was that carnosic acid (CA), a compound extracted from rosemary, was able to induce further expression of NQO1 through NF-E2 related factor 2 (NRF2) stabilization, thus significantly enhancing the cytotoxicity of β-lap in all of the melanoma cell lines tested. Taken together, the data presented in the current study indicated that the NRF2-NQO1 axis may have potential value as a therapeutic target in malignant melanoma to improve the rate of clinical response to NQO1-dependent antitumor drugs. IntroductionMalignant melanoma is one of the most aggressive forms of cancer, exhibiting resistance to various forms of chemotherapy.The global incidence and mortality rates of malignant melanoma are increasing (1-3). Novel targeted therapies designed to kill melanoma cells harboring mutations in B-Raf proto-oncogene, serine/threonine kinase (BRAF) have been developed using vemurafenib, which is a specific BRAF inhibitor (4,5). Missense mutations to the BRAF gene, most commonly a valine-to-glutamic acid substitution at codon 600, has been observed in ~80% of melanocytic nevi and ~50% of melanomas (6-9). In addition to this BRAF mutation, another therapeutic target has been investigated, as melanomas, including acral lentiginous melanoma, the most common type in ethnicities that produce high levels of melanin, have a low frequency of BRAF gene mutation (10,11). However, details of the mechanism responsible for the drug insensitivity of melanomas lacking BRAF mutations have been largely unclear. On the basis of the aforementioned background, a search for novel therapeutic strategies is justified.β-lapachone (β-lap), a lipophilic cytotoxic o-naphtoquinone derived from the bark of the South American Lapacho tree (Tabebuia avellanedae), has recently attracted attention as an antitumor drug (12,13). The mechanism of its antitumor effect is considered to involve the formation of reactive oxygen species (ROS) (13-15). ROS and other types of radicals are involved in a variety of biological phenomena, including tumorigenesis, degenerative disease and aging (16,17), and are also important medi...

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“…In addition to NFD, another quinone β-lapachone (β-LAP) has been documented to be present in trace amounts in the non-fractionated aqueous extracts of TA and TNM. This minor constituent, at higher pharmacological concentrations, exhibits anti-cancer activity in preclinical xeno-transplant models of epithelial organ site cancers via distinct molecular mechanisms (15,16,(39)(40)(41). However, it is important to recognize that at the low concentrations of TA or TNM used, the levels of β-LAP remain essentially undetectable (42).…”

Section: Discussionmentioning

confidence: 99%

Growth inhibitory efficacy and anti‑aromatase activity of Tabebuia avellanedae in a model for post‑menopausal Luminal A breast cancer

Telang¹,

Nair

Wong³

2019

biom rep

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Aromatase inhibitors (AIs) represent a treatment option for post-menopausal estrogen receptor-positive (ER +) breast cancer as monotherapy, or in combination with cyclin-dependent kinase 4/6 or mTOR inhibitors. Long-term treatment with these agents leads to dose-limiting toxicity and drug resistance. Natural substances provide testable alternatives to current therapy. Tabebuia avellanedae (TA) tree is indigenous to the Amazon rainforest. The inner bark of TA represents a medicinal dietary supplement known as Taheebo. Non-fractionated aqueous extract from TA is an effective growth inhibitor in the Luminal A and triple negative breast cancer models. The quinone derivative naphthofurandione (NFD) is a major bioactive agent in TA. The present study examined the efficacy of finely ground powder from the inner bark of TA, available under the name of Taheebo-NFD-Marugoto (TNM). The ER + MCF-7 cells stably transfected with the aromatase gene MCF-7 AROM represented a model for aromatase-expressing post-menopausal breast cancer. Anchorage-independent colony formation, cell cycle progression, pro-apoptotic caspase 3/7 activity, apoptosis-specific gene expression, aromatase activity and select estradiol (E 2) target gene expression represented the mechanistic end points. Treatment of MCF-7 AROM cells with TNM induced a dose-dependent reduction in E 2-promoted anchorage-independent colony number. Mechanistic assays on TNM-treated MCF-7 AROM cells demonstrated that TNM at a concentration of 10 µg (NFD content: 2 ng), induced S-phase arrest, increased pro-apoptotic caspase 3/7 activity, increased pro-apoptotic BAX and decreased anti-apoptotic BCL-2 gene expression, and inhibited aromatase activity. Additionally, TNM treatment downregulated ESR-1 (gene for ER-α), aromatase and progesterone gene expression and reduced mRNA levels of E 2 target genes pS2, GRB2 and cyclin D1. Inhibition of aromatase activity, based on the NFD content of TNM was superior to the clinical AIs Letrozole and Exemestane. These data demonstrated the potential efficacy of TNM as a nutritional alternative for current therapy of aromatase positive, post-menopausal breast cancer.

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β-lapachone suppresses the proliferation of human malignant melanoma cells by targeting specificity protein 1

Cited by 20 publications

References 54 publications

MicroRNA-18b inhibits the growth of malignant melanoma via inhibition of HIF-1α-mediated glycolysis

MicroRNA-18b inhibits the growth of malignant melanoma via inhibition of HIF-1α-mediated glycolysis

Carnosic acid, an inducer of NAD(P)H quinone oxidoreductase 1, enhances the cytotoxicity of β‑lapachone in melanoma cell lines

Growth inhibitory efficacy and anti‑aromatase activity of Tabebuia avellanedae in a model for post‑menopausal Luminal A breast cancer

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