Curcumin Analogue L48H37 Suppresses Human Osteosarcoma U2OS and MG-63 Cells’ Migration and Invasion in Culture by Inhibition of uPA via the JAK/STAT Signaling Pathway

Lu, Ko-Hsiu; Wu, Heng-Hsiung; Lin, Renn-Chia; Lin, Ya-Chiu; Lu, Peace Wun-Ang; Yang, Shun‐Fa; Yang, Jyh Bin

doi:10.3390/molecules26010030

Cited by 31 publications

(25 citation statements)

References 37 publications

(22 reference statements)

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“…For example, diphenyl difluoroketone (EF-24), with higher oral bioavailability (60%) than curcumin, was reported to trigger cell apoptosis in human acute myeloid leukemia cells [ 20 , 21 ]. In addition, L48H37, with a more stable structure than curcumin, can inhibit the migration and invasion ability of human osteosarcoma [ 22 ]. FLLL32 has better cytotoxicity than curcumin in colorectal cancer, glioblastoma, multiple myeloma, and liver cancer [ 12 ].…”

Section: Discussionmentioning

confidence: 99%

“…The MAPK pathway is an important signal pathway that regulates message transmission from outside the cell membrane to the nucleus, and it is closely related to cell proliferation, survival, differentiation, apoptosis, and other physiological processes [ 36 ]. Previous studies have pointed out that curcumin and its analogs promoted the apoptosis of cancer cells through the MAPK pathway and downstream caspase activation in several types of cancer [ 22 , 37 , 38 ]. In oral cancer, tetrahydrocurcumin (THC), a metabolite of curcumin, promoted G2/M arrest and apoptosis via the activation of the p38 pathway [ 39 ], and the curcumin analog DMC could also induce G2/M arrest and apoptosis through the p38 pathway.…”

Section: Discussionmentioning

confidence: 99%

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FLLL32 Triggers Caspase-Mediated Apoptotic Cell Death in Human Oral Cancer Cells by Regulating the p38 Pathway

Chuang

Chen

et al. 2021

IJMS

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Oral cancer is the most common oral malignant tumor in Taiwan. Although there exist several methods for treatment, oral cancer still has a poor prognosis and high recurrence. FLLL32, a synthetic analog of curcumin with antitumor activity, is currently known to induce melanoma apoptosis and inhibit tumor growth in various cancers. However, few studies have examined the mechanisms of FLLL32 in oral cancer. In this study, we explore whether FLLL32 induces apoptosis in oral cancer. We determined that FLLL32 can inhibit the cell viability of oral cancer. Next, we analyzed the effect of FLLL32 on the cell cycle of oral cancer cells and observed that the proportion of cells in the G2/M phase was increased. Additionally, annexin-V/PI double staining revealed that FLLL32 induced apoptosis in oral cancer cells. Data from the Human Apoptosis Array revealed that FLLL32 increases the expression of cleaved caspase-3 and heme oxygenase-1 (HO-1). FLLL32 activates proteins such as caspase-8, caspase-9, caspase-3, PARP, and mitogen-activated protein kinases (MAPKs) in apoptosis-related molecular mechanisms. Moreover, by using MAPK inhibitors, we suggest that FLLL32 induces the apoptosis of oral cancer cells through the p38 MAPK signaling pathway. In conclusion, our findings suggest that FLLL32 is a potential therapeutic agent for oral cancer by inducing caspase-dependent apoptosis and HO-1 activation through the p38 pathway. We believe that the activation of HO-1 and the p38 pathway by FLLL32 represent potential targets for further research in oral cancer.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

FLLL32 Triggers Caspase-Mediated Apoptotic Cell Death in Human Oral Cancer Cells by Regulating the p38 Pathway

Chuang

Chen

et al. 2021

IJMS

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“…JAK1 and JAK3 activate STATs by phosphorylation (21). It has been previously reported that JAK/STAT signaling is involved in several important cellular processes, including cell proliferation, migration, apoptosis and inflammation (41)(42)(43). A number of studies have suggested that JAK/STAT signaling is involved in the pathogenesis of tissue and organ I/R injury, including intestinal I/R injury (22)(23)(24).…”

Section: Discussionmentioning

confidence: 99%

Tofacitinib protects intestinal epithelial cells against oxygen‑glucose deprivation/reoxygenation injury by inhibiting the JAK/STAT3 signaling pathway

Yang

Xie

2021

Exp Ther Med

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The present study aimed to investigate the role and potential mechanism of action of tofacitinib (Tofa) in intestinal ischemia/reperfusion (I/R) injury. The normal rat small intestine epithelial cell line, IEC-6, was used to establish an I/R injury model by inducing oxygen-glucose deprivation/reoxygenation (OGD/R). Cells were divided into the following five groups: Control, OGD/R, OGD/R with 50, 100 and 200 nM Tofa. Following Tofa administration, cell viability was measured using Cell Counting Kit-8 assay and a lactate dehydrogenase detection kit. The expression levels of cell apoptosis-related proteins, Bcl-2, cleaved-caspase-3 and cleaved-caspase-9 were detected using western blot analysis. Additionally, the levels of oxidative stress-related markers, such as reactive oxygen species (ROS), malondialdehyde (MDA) and superoxide dismutase (SOD), and inflammatory cytokines, TNF-α, IL-6 and IL-1β were assessed using the colorimetric method. Western blot analysis was also used to measure the expression levels of the Janus kinase (JAK)/STAT3 signaling pathway-related proteins, including phosphorylated (p)-JAK1, p-JAK3 and p-STAT3. Subsequently, colivelin, an agonist of the JAK/STAT3 pathway, was used to investigate whether the effects of Tofa on intestinal I/R injury were mediated by this signaling pathway. The results showed that Tofa dose-dependently elevated cell viability compared with that in the OGD/R group. By contrast, Tofa attenuated cell apoptosis, which was coupled with upregulated Bcl-2 expression, downregulated cleaved-caspase-3 and downregulated cleaved-caspase-9 levels, in OGD/R-induced IEC-6 cells. Furthermore, the contents of ROS and MDA were significantly increased following exposure to OGD/R, which were accompanied by the decreased activity of SOD. These effects were reversed following cell treatment with Tofa. Consistently, Tofa intervention reduced the secretion levels of TNF-α, IL-6 and IL-1β in a dose-dependent manner. Additionally, Tofa markedly downregulated the phosphorylation levels of JAK1, JAK3 and STAT3 in OGD/R-induced IEC-6 cells. However, treatment with colivelin markedly reversed the inhibitory effects of Tofa on cell viability, cell apoptosis, oxidative stress and inflammation. Overall, the findings of the present study suggested that Tofa could protect against intestinal I/R injury by inhibiting the JAK/STAT3 signaling pathway, which may hold promise as a therapeutic agent for intestinal I/R injury.

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“…FLLL32 however showed very little inhibition of RTKs like EGFR, HER2 and Met ( Lin et al, 2010b ). Another curcumin analogue, L48H37, also decreased the phosphorylation of JAK1, JAK2, JAK3, and STAT3 in osteosarcoma cells ( Lu et al, 2020 ). Gene expression profiling and recent RNA sequencing technology also identified both upregulation and downregulation of JAK/STAT signaling pathway components, with some of these studies also documenting changes in RTK gene expression ( Van Erk et al, 2004 ; Teiten et al, 2009 ; Zhao W. et al, 2015 ).…”

Section: Receptor Tyrosine Kinase Signaling Pathways Targeted By Curcumin In Cancermentioning

confidence: 99%

Receptor Tyrosine Kinases and Their Signaling Pathways as Therapeutic Targets of Curcumin in Cancer

et al. 2021

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Receptor tyrosine kinases (RTKs) are transmembrane cell-surface proteins that act as signal transducers. They regulate essential cellular processes like proliferation, apoptosis, differentiation and metabolism. RTK alteration occurs in a broad spectrum of cancers, emphasising its crucial role in cancer progression and as a suitable therapeutic target. The use of small molecule RTK inhibitors however, has been crippled by the emergence of resistance, highlighting the need for a pleiotropic anti-cancer agent that can replace or be used in combination with existing pharmacological agents to enhance treatment efficacy. Curcumin is an attractive therapeutic agent mainly due to its potent anti-cancer effects, extensive range of targets and minimal toxicity. Out of the numerous documented targets of curcumin, RTKs appear to be one of the main nodes of curcumin-mediated inhibition. Many studies have found that curcumin influences RTK activation and their downstream signaling pathways resulting in increased apoptosis, decreased proliferation and decreased migration in cancer both in vitro and in vivo. This review focused on how curcumin exhibits anti-cancer effects through inhibition of RTKs and downstream signaling pathways like the MAPK, PI3K/Akt, JAK/STAT, and NF-κB pathways. Combination studies of curcumin and RTK inhibitors were also analysed with emphasis on their common molecular targets.

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Curcumin Analogue L48H37 Suppresses Human Osteosarcoma U2OS and MG-63 Cells’ Migration and Invasion in Culture by Inhibition of uPA via the JAK/STAT Signaling Pathway

Cited by 31 publications

References 37 publications

FLLL32 Triggers Caspase-Mediated Apoptotic Cell Death in Human Oral Cancer Cells by Regulating the p38 Pathway

FLLL32 Triggers Caspase-Mediated Apoptotic Cell Death in Human Oral Cancer Cells by Regulating the p38 Pathway

Tofacitinib protects intestinal epithelial cells against oxygen‑glucose deprivation/reoxygenation injury by inhibiting the JAK/STAT3 signaling pathway

Receptor Tyrosine Kinases and Their Signaling Pathways as Therapeutic Targets of Curcumin in Cancer

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