Siegesbeckia orientalis Extract Inhibits TGFβ1-Induced Migration and Invasion of Endometrial Cancer Cells

Chang, Chi‐Chang; Ling, Xue-Hua; Hsu, Hsia-Fen; Wu, Jian; Wang, Chao-Ping; Yang, Jyh-Ferng; Fang, Liwen; Houng, Jer-Yiing

doi:10.3390/molecules21081021

Cited by 24 publications

(31 citation statements)

References 36 publications

(45 reference statements)

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“…Even though we could not find a plausible molecular mechanism for the synergistic anti-invasive effect of the narrow dose window of metformin (0-100 μM) and MPA combination in Ishikawa cells (Fig 3B), it is notable that MMP-9 and TGF-β1 showed the same pattern of change to that of cell invasion only in KLE cells (Fig 4 and 5). MMP is known as one of the most essential proteases in the proteolysis of extracellular matrix proteins and plays important roles in invasion and migration (21). Unlike other relevant studies of MMPs in which the results were the same in MMP-2 and MMP-9 (21-23), the results of our study were specific to MMP-9, but not MMP-2.…”

Section: Discussionmentioning

confidence: 99%

“…MMP is known as one of the most essential proteases in the proteolysis of extracellular matrix proteins and plays important roles in invasion and migration (21). Unlike other relevant studies of MMPs in which the results were the same in MMP-2 and MMP-9 (21-23), the results of our study were specific to MMP-9, but not MMP-2. TGF-β has also been extensively studied as a crucial cytokine which promotes endometrial cancer invasion and metastasis via epithelial mesenchymal transition (21, 23, 24).…”

Section: Discussionmentioning

confidence: 99%

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Medroxyprogesterone reverses tolerable dose metformin-induced inhibition of invasion via matrix metallopeptidase-9 and transforming growth factor-β1 in KLE endometrial cancer cells

Suh

Lee

Park

et al. 2019

Preprint

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18This study was performed to evaluate the anticancer effects of tolerable doses of metformin 19 with or without medroxyprogesterone (MPA) in endometrial cancer cells. Cell viability, cell 20 invasion, and levels of matrix metallopeptidase (MMP) and transforming growth factor (TGF)-21 β1 were analyzed using three human endometrial adenocarcinoma cell lines (Ishikawa, KLE, 22 and USPC) after treatment with different dose combinations of MPA (0, 10 µM) and metformin 23 (0, 100, 1000 µM). Combining metformin (0, 100, 1000 µM) and 10 µM MPA induced 24 significantly decreased cell viability in a time-and dose-dependent manner in Ishikawa cells, 25 but not in KLE and USPC cells. There was no dose-or time-dependent cell growth inhibition, 26 or positive western blot results for the expression of progesterone receptors and phospho-27 AMPKα, following treatment with any combination of metformin (0, 100, 1000 µM) and 10 28 µM MPA in KLE and USPC cells. In KLE cells, metformin treatment alone significantly 29 inhibited cell invasion in a dose-dependent manner (1.31±0.05, 0.94±0.04, 0.83±0.05 at 0, 100 30 µM, 1000 µM, respectively; p<0.0005). The inhibitory effect of metformin was reversed to 31 create a stimulating effect when metformin was combined with 10 µM MPA (1.10±0.05, 32 1.42±0.18, 1.41±0.26 at 0, 100, 1000 µM, respectively; p<0.005). MMP-9 and TGF-β1 showed 33 similar trends in terms of cell invasion in KLE cells. In conclusion, the anti-invasive effect of 34 metformin in KLE cells was completely reversed to the state of no treatment by the addition of 35 MPA; this might be mediated through MMP-9 and TGF-β1. Our study suggests the possibility 36 of these combinations doing harm, rather than good, under some conditions. 3 37Recently, metformin, an oral biguanide anti-diabetic drug for type 2 diabetes, was 55 shown to have significant anticancer activity and considered a novel treatment option through 56 drug repositioning (4), including for endometrial cancer (5-7). However, it should be noted that 57 almost all previous studies were conducted with supra-pharmacological concentrations (doses) 58 of metformin, that is, 10-100 times higher than maximally achievable therapeutic 59 concentrations found in patients with type 2 diabetes mellitus (8). Such levels exceed the 4 60 maximum dose that could cause lactic acidosis, one of the most serious side effects of 61 metformin. Any anticancer effect of metformin should be studied only in the condition of 62 achievable therapeutic concentrations (8, 9). 63Another approach for the development of novel anticancer drug regimens is the use of 64 drug combinations. Although hormonal therapy is currently recommended only for lower-65 grade endometrioid histology in clinical guidelines, there is evidence suggesting several 66 anticancer mechanisms of progestational agents, which could show significant effects in 67 poorly-differentiated endometrioid adenocarcinoma, as well as USPC (2, 10, 11), particularly 68 when combined with metformin (12). 69The purpose of this study w...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Medroxyprogesterone reverses tolerable dose metformin-induced inhibition of invasion via matrix metallopeptidase-9 and transforming growth factor-β1 in KLE endometrial cancer cells

Suh

Lee

Park

et al. 2019

Preprint

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“…By comparing cell migration through coated and non‐coated microporous membranes, the invasive index can easily be determined (Chen, ; Valster et al, ). The Boyden chamber assay was used to monitor inhibition of endometrial cancer cell invasion (RL95‐2 and HEC‐1A) by an ethanol extract of Siegesbeckia orientalis aerial parts by Chang, Ling, et al (). In another study, the same assay has been used to determine the inhibition of human non‐small cell lung cancer cell migration by a small molecule, 6,7‐dimethyl‐4‐(3,4,5‐trimethoxyphenyl)‐3,4‐dihydroquinolin‐2 (1H)‐one Park, Lee and Lee ().…”

Section: Cell Migration and Invasion Assaysmentioning

confidence: 99%

In vitro assays and techniques utilized in anticancer drug discovery

Ediriweera

Tennekoon

Samarakoon

2018

J of Applied Toxicology

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Development of a cancer is a multistep process and six major hallmarks of cancer that are known to control malignant transformation have been described. Anticancer drug development is a tedious process, requiring a number of in vitro, in vivo and clinical studies. In vitro assays provide an initial platform for cancer drug discovery approaches. A wide range of in vitro assays/techniques have been developed to evaluate each hallmark feature of cancer and selection of a particular in vitro assay or technique mainly depends on the specific research question (s) to be examined. In the present review, we have described some commonly utilized in vitro assays and techniques used to examine cell viability/proliferation, apoptosis, cellular senescence, invasion and migration, oxidative stress and antioxidant effects, gene and protein expression, angiogenesis and genomic alterations in cancer drug discovery. Additionally, uses of modern techniques such as high throughput screening, high content screening and reporter gene assays in cancer drug discovery have also been described.

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“…Siegesbeckia orientalis Linne is a traditionally used Chinese medicinal herb that exhibits various pharmacological activities. Its ethanol extract (SOE) has been reported as a potential anti-metastatic agent by reversing the TGFβ1-induced EMT via ERK1/2, JNK1/2, and Akt pathways [36]. SOE can inhibit the migration and invasion of endometrial cancer RL95-2 and HEC-1A cells in a dose-dependent manner.…”

Section: Suppression Of Epithelial-mesenchymal Transitionmentioning

confidence: 99%

Recent Progress on the Molecular Mechanisms of Anti-invasive and Metastatic Chinese Medicines for Cancer Therapy

Wei¹,

Wang²,

Feng³

2017

Unique Aspects of Anti-Cancer Drug Development

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Despite of the recent advances in diagnostic and therapeutic approaches, cancer remains as the leading cause of death worldly with diverse causal factors regarding genes and environment. Invasion and metastasis, as one of the most important hallmarks for cancer, have restrained the successful clinical therapy and are the primary causes of death among cancer patients. So far, most chemotherapeutic drugs are not effective for metastatic cancer due to drug resistance and serious side effects. Therefore, it is urgently essential to develop more effective therapeutic methods. Owing to their diverse biological activities and low toxicity, naturally active compounds derived from Chinese medicines, as a complementary and alternative approach, are reported to promote the therapeutic index and provoked as an excellent source for candidates of anti-metastatic drugs. With the rapid development of molecular biology techniques, the molecular mechanisms of the effects of potential anti-invasive and metastatic Chinese medicines are gradually elucidated. This chapter reviews the potential anti-invasive and metastatic mechanisms of naturally active compounds from Chinese medicines, including suppression of EMT, proteases and cancer-induced angiogenesis, anoikis regulation of circulating tumor cells and regulation of miRNA-mediated gene expression, providing scientific evidence for clinically using Chinese medicines in the field of cancer therapy.

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Siegesbeckia orientalis Extract Inhibits TGFβ1-Induced Migration and Invasion of Endometrial Cancer Cells

Cited by 24 publications

References 36 publications

Medroxyprogesterone reverses tolerable dose metformin-induced inhibition of invasion via matrix metallopeptidase-9 and transforming growth factor-β1 in KLE endometrial cancer cells

Medroxyprogesterone reverses tolerable dose metformin-induced inhibition of invasion via matrix metallopeptidase-9 and transforming growth factor-β1 in KLE endometrial cancer cells

In vitro assays and techniques utilized in anticancer drug discovery

Recent Progress on the Molecular Mechanisms of Anti-invasive and Metastatic Chinese Medicines for Cancer Therapy

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