ABT-737 Induces Expression of the Death Receptor 5 and Sensitizes Human Cancer Cells to TRAIL-induced Apoptosis

Indirubin-3′-monoxime (I3M) exhibits anti-proliferative activity in various cancer cells; however, its anti-cancer mechanism remains incompletely elucidated. This study revealed that I3M promotes the expression of death receptor 5 (DR5) and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) in HCT116 p53+/+ cells, resulting in caspase-mediated apoptosis. However, this study demonstrated that HCT116 p53-/- cells are insensitive to I3M-mediated apoptosis, indicating that I3M-induced apoptosis depends on the p53 status of HCT116 cells. Additionally, in HCT116 p53-/- cells, I3M significantly increased Ras expression, while in HCT116 p53+/+ cells, it reduced Ras expression. Furthermore, I3M remarkably increased the production of reactive oxygen species (ROS), which were reduced in transient p53 knockdown, indicating that I3M-mediated apoptosis is promoted by p53-mediated ROS production. Our results also showed that I3M enhanced transcription factor C/EBP homologous protein (CHOP) expression, resulting in endoplasmic reticulum (ER) stress-mediated DR5 expression, which is upregulated by ROS production in HCT116 p53+/+ cells. Moreover, co-treatment with TRAIL synergistically enhanced I3M-induced DR5 expression, thereby triggering TRAIL-induced apoptosis of HCT116 p53+/+ cells, which was interfered by a DR5-specific blocking chimeric antibody. In summary, I3M potently enhances TRAIL-induced apoptosis by upregulating DR5 expression via p53-mediated ROS production in HCT116 p53+/+ cells. However, HCT116 p53-/- cells were resistant to I3M-mediated apoptosis, suggesting that I3M could be a promising anti-cancer candidate against TRAIL-resistant p53+/+ cancer cells.

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Artemisinin Derivatives Stimulate DR5-Specific TRAIL-Induced Apoptosis by Regulating Wildtype P53

Cancers ◽

10.3390/cancers12092514 ◽

2020 ◽

Vol 12 (9) ◽

pp. 2514

Author(s):

Xinyu Zhou ◽

Sietske N. Zijlstra ◽

Abel Soto-Gamez ◽

Rita Setroikromo ◽

Wim J. Quax

Keyword(s):

Colon Cancer ◽

Cancer Cells ◽

Death Receptor ◽

Dependent Manner ◽

Death Receptor 5 ◽

Novel Therapy ◽

Artemisinin Derivatives ◽

The Status ◽

Cervical Cancer Cells ◽

Induced Apoptosis

Artemisinin derivatives, widely known as commercial anti-malaria drugs, may also have huge potential in treating cancer cells. It has been reported that artemisinin derivatives can overcome resistance to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in liver and cervical cancer cells. In our study, we demonstrated that artesunate (ATS) and dihydroartemisinin (DHA) are more efficient in killing colon cancer cells compared to artemisinin (ART). ATS/DHA induces the expression of DR5 in a P53 dependent manner in HCT116 and DLD-1 cells. Both ATS and DHA overcome the resistance to DHER-induced apoptosis in HCT116, mainly through upregulating death receptor 5 (DR5). We also demonstrate that DHA sensitizes HCT116 cells to DHER-induced apoptosis via P53 regulated DR5 expression in P53 knockdown assays. Nevertheless, a lower effect was observed in DLD-1 cells, which has a single Ser241Phe mutation in the P53 DNA binding domain. Thus, the status of P53 could be one of the determinants of TRAIL resistance in some cancer cells. Finally, the combination treatment of DHA and the TRAIL variant DHER increases cell death in 3D colon cancer spheroid models, which shows its potential as a novel therapy.

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Luteolin sensitizes human liver cancer cells to TRAIL‑induced apoptosis via autophagy and JNK‑mediated death receptor 5 upregulation

International Journal of Oncology ◽

10.3892/ijo.2018.4633 ◽

2018 ◽

Cited By ~ 2

Author(s):

Uddin Nazim ◽

Sang‑Youel Park

Keyword(s):

Liver Cancer ◽

Cancer Cells ◽

Human Liver ◽

Death Receptor ◽

Death Receptor 5 ◽

Liver Cancer Cells ◽

Human Liver Cancer ◽

Induced Apoptosis ◽

Human Liver Cancer Cells

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Parthenolide enhances sensitivity of colorectal cancer cells to TRAIL by inducing death receptor 5 and promotes TRAIL-induced apoptosis

International Journal of Oncology ◽

10.3892/ijo.2014.2795 ◽

2014 ◽

Vol 46 (3) ◽

pp. 1121-1130 ◽

Cited By ~ 13

Author(s):

SE-LIM KIM ◽

YU-CHUAN LIU ◽

YOUNG RAN PARK ◽

SEUNG YOUNG SEO ◽

SEONG HUN KIM ◽

...

Keyword(s):

Colorectal Cancer ◽

Cancer Cells ◽

Death Receptor ◽

Death Receptor 5 ◽

Colorectal Cancer Cells ◽

Induced Apoptosis

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FoxM1 knockdown sensitizes human cancer cells to proteasome inhibitor-induced apoptosis but not to autophagy

Cell Cycle ◽

10.4161/cc.10.19.17735 ◽

2011 ◽

Vol 10 (19) ◽

pp. 3269-3273 ◽

Cited By ~ 20

Author(s):

Bulbul Pandit ◽

Andrei L. Gartel

Keyword(s):

Cancer Cells ◽

Proteasome Inhibitor ◽

Human Cancer ◽

Human Cancer Cells ◽

Induced Apoptosis

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DOX-Vit D, a Novel Doxorubicin Delivery Approach, Inhibits Human Osteosarcoma Cell Proliferation by Inducing Apoptosis While Inhibiting Akt and mTOR Signaling Pathways

Pharmaceutics ◽

10.3390/pharmaceutics10030144 ◽

2018 ◽

Vol 10 (3) ◽

pp. 144 ◽

Cited By ~ 7

Author(s):

Zaid Maayah ◽

Ti Zhang ◽

Marcus Forrest ◽

Samaa Alrushaid ◽

Michael Doschak ◽

...

Keyword(s):

Cell Proliferation ◽

Cancer Cells ◽

Signaling Pathways ◽

Human Cancer ◽

Death Receptor ◽

Osteosarcoma Cell ◽

Acquired Drug Resistance ◽

Human Cancer Cells ◽

Mg63 Cells ◽

Delivery Approach

Doxorubicin (DOX) is a very potent and effective anticancer agent. However, the effectiveness of DOX in osteosarcoma is usually limited by the acquired drug resistance. Recently, Vitamin D (Vit-D) was shown to suppress the growth of many human cancer cells. Taken together, we synthesized DOX-Vit D by conjugating Vit-D to DOX in order to increase the delivery of DOX into cancer cells and mitigate the chemoresistance associated with DOX. For this purpose, MG63 cells were treated with 10 µM DOX or DOX-Vit D for 24 h. Thereafter, MTT, real-time PCR and western blot analysis were used to determine cell proliferation, genes and proteins expression, respectively. Our results showed that DOX-Vit D, but not DOX, significantly elicited an apoptotic signal in MG63 cells as evidenced by induction of death receptor, Caspase-3 and BCLxs genes. Mechanistically, the DOX-Vit D-induced apoptogens were credited to the activation of p-JNK and p-p38 signaling pathway and the inhibition of proliferative proteins, p-Akt and p-mTOR. Our findings propose that DOX-Vit D suppressed the growth of MG63 cells by inducing apoptosis while inhibiting cell survival and proliferative signaling pathways. DOX-Vit D may serve as a novel drug delivery approach to potentiate the delivery of DOX into cancer cells.

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