Evodiamine selectively targets cancer stem-like cells through the p53-p21-Rb pathway

Han, Seula; Woo, Jong Kyu; Jung, Yuchae; Jeong, Dawoon; Kang, Min‐Sook; Yoo, Young-Ji; Lee, Hani; Oh, Seung Hyun; Ryu, Jae‐Ha; Kim, Woo Young

doi:10.1016/j.bbrc.2015.12.066

Cited by 39 publications

(31 citation statements)

References 29 publications

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“…However, those studies focused on the fast-growing cancer cells, BCCs. Recently, we found that, in comparable concentrations, this compound modulates the p53-p21-Rb pathways only in breast CSCs but not in BCCs holding them at G1 stage [13], and we hypothesized that evodiamine may also target the colon cancer cells.…”

Section: Introductionmentioning

confidence: 98%

Evodiamine Eliminates Colon Cancer Stem Cells via Suppressing Notch and Wnt Signaling

Kim

Choi

et al. 2019

Molecules

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Evodiamine, an alkaloid contained in traditional Asian herbal medicines that have been used for hundreds years, is interesting due to its cytotoxic effects against many cancers. We examined the effect of evodiamine on the cancer stem cell (CSC) population and the bulk cultured cancer cells (BCC) of colon cancers to examine the double targeting effect. We found that three colon cancer cell lines’ BCC and CSC are effectively targeted by evodiamine. Evodiamine was able to suppress BCC proliferation and induce apoptosis of the cells captured in G2/M phase, as previously reported. However, evodiamine did not cause the accumulation of CSCs at a certain stage of the cell cycle, resulting in the elimination of stemness through an unknown mechanism. By analyzing the expression of 84 genes related to CSCs in two colon cancer cell lines’ CSC, as well as performing further informatics analyses, and quantitative RT-PCR analyses of 24 CSC genes, we found that evodiamine suppressed the expression of the genes that control key signaling pathways of CSC, namely, WNT and NOTCH signaling, to lead CSC elimination. These results suggest that evodiamine should be further developed for targeting both BCCs and CSCs in colon cancers.

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Section: Introductionmentioning

confidence: 98%

Evodiamine Eliminates Colon Cancer Stem Cells via Suppressing Notch and Wnt Signaling

Kim

Choi

et al. 2019

Molecules

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“…In previous years, there have been multiple publications focusing on various aspects of EVO, in terms of its effects on proliferation, apoptosis and autophagy (12)(13)(14). As the main component of the Chinese medicine formulation Evodia (15), EVO has inhibitory effects on cervical, lung, colon and nasopharyngeal cancer and other tumor types, likely mediated by the inhibition of tumor proliferation, metastasis and angiogenesis and the promotion of tumor cell apoptosis and autophagy (16). The present study was conducted to determine the effects of EVO on the proliferation, apoptosis and autophagy of human PC cell lines and an in situ xenograft model of PC in nude mice, and to investigate its possible mechanism of action.…”

Section: Introductionmentioning

confidence: 99%

Effects of evodiamine on PI3K/Akt and MAPK/ERK signaling pathways in pancreatic cancer cells

et al. 2020

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The effective antitumor drug evodiamine (EVO) is attracting increased attention. Therefore, the present study aimed to investigate the effects of EVO on the proliferation, apoptosis and autophagy of human pancreatic cancer (PC) cell lines in vitro and in vivo. Human PANC-1 and SW1990 PC cell lines were treated with different concentrations of EVO and proliferation was detected using a Cell Counting Kit (CCK)-8 assay. Colony formation and wound-healing assays showed that EVO inhibited PC cell viability and migration, and apoptosis was detected using flow cytometry. Western blotting and immunofluorescence detected the expression of proteins in PANC-1 and SW1990 cells. The PANC-1 cells were used to establish an orthotopic pancreatic tumor model in nude mice. Tumor-bearing nude mice were administered with different concentrations of EVO, and growth was monitored. High-resolution positron emission tomography and fluorine-18-labeled fluorodeoxyglucose were used to monitor the tumor/non-tumor (T/NT) ratio and standard uptake value (SUV) of the mice, which were subsequently sacrificed to measure the transplanted tumor weight. Apoptosis increased with increasing EVO concentration. The EVO-treated PC cells exhibited significantly higher expression of LC3II than the controls cells. EVO decreased LC3II, enhanced P62 and inhibited the expression of Akt, extracellular-signal-regulated protein kinase (ERK)1/2 and p38. Compared with the control group, the T/NT ratio, SUV and tumor weight decreased more markedly in the EVO-treated group. The tumor expression of phosphorylated AKT, detected using immunohistochemistry, decreased with increasing EVO doses in vivo. EVO induced PC cell apoptosis by inhibiting phosphoinositide 3-kinase/AKT and mitogen-activated protein kinase/ERK and inhibiting the phosphorylation of signal transducer and activator of transcription activator 3 in PC cells to inhibit autophagy, suggesting that EVO may be considered as a novel PC treatment.

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“…10) We also demonstrated that effective inhibitors of cell survival in growth factor-deprived conditions, as opposed to fetal bovine serum (FBS)-supplemented conditions, can halt cells at the G1/S checkpoint. We recently found that some known anti-proliferative reagents confer CSC-specific activity at a lower concentration 11,12) ; thus, we hypothesized that 2-aminodihydroquinoline compounds may have anti-CSC activity regardless of the cytotoxic effect that we previously described. Upon study of CSCs of a glioblastoma cell line, we found that 2 compounds out of 10 tested have strong anti-CSC effects with very distinctive molecular pathways.…”

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confidence: 86%

“…The bulk cultured cells were seeded onto a well of 96 well plates (2000/well) before the drug treatment. CSCs (1500/a 96 well) were cultured in suspension in poly(2-hydroxyethyl methacrylate) coated 96 well plate 16) with CSC specific medium, described previously 12) with or without the compounds. The CSC spheres were counted when the most of the sphere's diameter in control group reached to 100 µm (after 6 d).…”

Section: Bulk Cell Culture and Csc Culture Inhibition Analysesmentioning

confidence: 99%

“…12,19,20) Briefly, U87 (5×10 5 cells/mL) was seeded and treated with DMSO or compounds (5 µM) using sphere culture medium in 100 mm dishes. The cells dissociated from the CSC spheroid culture by trypsin were suspended in ALDEFLUOR assay buffer containing ALDH substrate (BAAA, 1 µM for 1×10 6 /mL cells) and incubated during 60 min at 37°C.…”

Section: Bulk Cell Culture and Csc Culture Inhibition Analysesmentioning

confidence: 99%

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Selective Targeting of Cancer Stem Cells by 2-Aminodihydroquinoline Analogs

Park

Kim

et al. 2017

CHEMICAL & PHARMACEUTICAL BULLETIN

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Many aminodihydroquinoline compounds have been studied to determine their cytotoxicity to cancer cells. However, anti-cancer stem cells (CSCs) activity of aminodihydroquinoline has not been tested in spite that CSC is believed to do an important roles in chemotherapy resistance and recurrence. The CSC selective targeting activities of 10 recently synthesized 2-aminodihydroquinoline analogs were examined on CSCs and bulk culture of a glioblastoma cell line. A diethylaminopropyl substituted aminodihydroquinoline, 5h, showed a strong anti-CSC effect and general cytotoxicity. However, a benzyl substituted aminodihydroquinoline, 5i, displayed the most effective anti-CSC effect, with no or small significant cytotoxic effect in bulk culture conditions. While 5h temporarily enhanced CSC marker-positive cells and eventually suppressed the CSC population, which is similar to other cytotoxic anticancer reagents reported, 5i selectively eliminated CSC marker-positive cells based on fluorescence activated cell sorter (FACS) analysis. 5h also temporarily activated some genes associated with signaling required for CSC, while 5i selectively suppressed these genes supporting that the differential effects are resulted from different molecular responses. In addition, the selective CSC effect is also found against a colon cancer cell line. Collectively, we suggest that these two novel aminodihydroquinoline compounds possess novel anti-CSC effects in colon and brain tumor derived cell lines probably through independent pathways. Key words 2-aminodihydroquinoline; cancer stem cell; selective targeting More than 50 years ago, it was noted that heterogeneous cell populations may exist in a tumor, and that in vivo tumor intimating cells are only a small portion of the tumor.1,2) These tumor initiating cells have been isolated from most types of tumors. These cells are now referred to as cancer stem cells (CSC) because they share many characteristics with tissue stem cells and mediate stem-like roles in cancer.2) Due to the critical roles of CSCs in chemotherapy and radiotherapy resistance, many pre-clinical studies and clinical trials have been undertaken to develop new strategies to eliminate CSCs. 3)Several novel compounds have been developed and are under evaluation as CSC therapeutics (reviewed in Jung et al. 3)). The majority of currently used clinical anti-cancer reagents target the fast proliferation effect of cancer cells. Most of those chemo-therapeutic agents have been developed based on their cytotoxic effect since the first chemotherapeutic agent, aminopterin, was used for leukemia in 1947. 4,5) Since then, hundreds of thousands of chemicals have been developed as cancer therapies to target cancer cell cycle. However, acquired resistance is the most serious problem for virtually all currently used chemotherapeutic agents. Therefore, to overcome chemo-resistance, anti-CSC agents need to be urgently developed. Aminodihydroquinoline analogs have attracted attention in drug discovery due to their variable range of biological act...

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Evodiamine selectively targets cancer stem-like cells through the p53-p21-Rb pathway

Cited by 39 publications

References 29 publications

Evodiamine Eliminates Colon Cancer Stem Cells via Suppressing Notch and Wnt Signaling

Evodiamine Eliminates Colon Cancer Stem Cells via Suppressing Notch and Wnt Signaling

Effects of evodiamine on PI3K/Akt and MAPK/ERK signaling pathways in pancreatic cancer cells

Selective Targeting of Cancer Stem Cells by 2-Aminodihydroquinoline Analogs

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