Synergistic effects of rmhTRAIL and 17-AAG on the proliferation and apoptosis of multiple myeloma cells

Wang, Jing; Li, Yun; Sun, Wei; Liu, Jing; Chen, Wen-Ming

doi:10.1080/10245332.2018.1449338

Cited by 8 publications

(6 citation statements)

References 25 publications

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“…Thus, RPMI-8226 and SKO-007 cells were considered resistant to cyclopamine. As described in a previous study, RPMI-8226 cells were sensitive to CPT (24). The inhibitory rate of low-dose treatment was >50% and that of the high dose was ~80%.…”

Section: Cpt Ng/ml -------------------------------------------------supporting

confidence: 59%

Cyclopamine sensitizes multiple myeloma cells to circularly permuted TRAIL‑induced apoptosis

et al. 2021

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Tumor necrosis factor related apoptosis inducing ligand (TRAIL) is a promising anti-myeloma drug prototype. The aim of the present study was to investigate the synergistic effects of cyclopamine and circularly permuted TRAIL (CPT) on the proliferation and apoptosis of multiple myeloma cells. The results showed that the inhibitory effects of cyclopamine on the proliferation of human myeloma RPMI-8226 and SKO-007 cells were weak. RPMI-8226 cells were sensitive to CPT; however, the proliferation of SKO-007 cells was not effectively inhibited by CPT. SKO-007 cells were thus considered resistant to cyclopamine and CPT and used for subsequent experiments. Treatment with a combination of cyclopamine and CPT significantly inhibited cell proliferation. Moreover, the Q value showed that cyclopamine combined with CPT could synergistically inhibit the proliferation of SKO-007 cells. Cyclopamine increased CPT-induced apoptosis in the SKO-007 cells and exhibited a synergistic induction of apoptosis when combined with CPT. Moreover, the combination of cyclopamine and CPT decreased the ratio of myeloma stem cells. Quantitative PCR showed that cyclopamine decreased the mRNA expression levels of GLI1/GLI2/GLI3 and increased the expression levels of death receptor 4. In conclusion, the present study showed that a combination of cyclopamine and CPT exhibited synergistic effects on the inhibition of proliferation and induction of apoptosis in myeloma cells.

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Section: Cpt Ng/ml -------------------------------------------------supporting

confidence: 59%

Cyclopamine sensitizes multiple myeloma cells to circularly permuted TRAIL‑induced apoptosis

et al. 2021

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“…Furthermore, claspin has also been previously reported as a negative regulator of DNA replication inhibited by PERK [ 47 ]. Finally, several highly upregulated proteins such as TRAIL, BAD and HTRA2 have been extensively studied as being apoptotic drivers in MM [ 48 , 49 , 50 , 51 , 52 ].…”

Section: Discussionmentioning

confidence: 99%

Characterization of a PERK Kinase Inhibitor with Anti-Myeloma Activity

Bagratuni

Patseas

Mavrianou-Koutsoukou

et al. 2020

Cancers

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Due to increased immunoglobulin production and uncontrolled proliferation, multiple myeloma (MM) plasma cells develop a phenotype of deregulated unfolded protein response (UPR). The eIF2-alpha kinase 3 [EIF2αK3, protein kinase R (PKR)-like ER kinase (PERK)], the third known sensor of endoplasmic reticulum (ER) stress, is a serine-threonine kinase and, like the other two UPR-related proteins, i.e., IRE1 and ATF6, it is bound to the ER membrane. MM, like other tumors showing uncontrolled protein secretion, is highly dependent to UPR for survival; thus, inhibition of PERK can be an effective strategy to suppress growth of malignant plasma cells. Here, we have used GSK2606414, an ATP-competitive potent PERK inhibitor, and found significant anti-proliferative and apoptotic effects in a panel of MM cell lines. These effects were accompanied by the downregulation of key components of the PERK pathway as well as of other UPR elements. Consistently, PERK gene expression silencing significantly increased cell death in MM cells, highlighting the importance of PERK signaling in MM biology. Moreover, GSK2606414, in combination with the proteasome inhibitor bortezomib, exerted an additive toxic effect in MM cells. Overall, our data suggest that PERK inhibition could represent a novel combinatorial therapeutic approach in MM.

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“…In this study, in vitro experiments on two different CRC cell lines were performed for this purpose. Referring to existing literature, the combination index Q [32] and Bliss independent model [33] were applied for the evaluation of the synergism.…”

Section: Validation For the Synergistic Effect Between Mk-2206 And Cp...mentioning

confidence: 99%

Discovery of Synergistic Drug Combinations for Colorectal Cancer Driven by Tumor Barcode Derived from Metabolomics “Big Data”

Xing

et al. 2022

Metabolites

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The accumulation of cancer metabolomics data in the past decade provides exceptional opportunities for deeper investigations into cancer metabolism. However, integrating a large amount of heterogeneous metabolomics data to draw a full picture of the metabolic reprogramming and to discover oncometabolites of certain cancers remains challenging. In this study, a tumor barcode constructed based upon existing metabolomics “big data” using the Bayesian vote-counting method is proposed to identify oncometabolites in colorectal cancer (CRC). Specifically, a panel of oncometabolites of CRC was generated from 39 clinical studies with 3202 blood samples (1332 CRC vs. 1870 controls) and 990 tissue samples (495 CRC vs. 495 controls). Next, an oncometabolite-protein network was constructed by combining the tumor barcode and its involved proteins/enzymes. The effect of anti-cancer drugs or drug combinations was then mapped into this network by the random walk with restart process. Utilizing this network, potential Irinotecan (CPT-11)-sensitizing agents for CRC treatment were discovered by random forest and Xgboost. Finally, a compound named MK-2206 was highlighted and its synergy with CPT-11 was validated on two CRC cell lines. To summarize, we demonstrate in the present study that the metabolomics “big data”-based tumor barcodes and the subsequent network analyses are potentially useful for drug combination discovery or drug repositioning.

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Synergistic effects of rmhTRAIL and 17-AAG on the proliferation and apoptosis of multiple myeloma cells

Abstract: The combined application of rmhTRAIL and 17-AAG revealed favorable synergistic effects in the treatment of MM.

Cited by 8 publications

References 25 publications

Cyclopamine sensitizes multiple myeloma cells to circularly permuted TRAIL‑induced apoptosis

Cyclopamine sensitizes multiple myeloma cells to circularly permuted TRAIL‑induced apoptosis

Characterization of a PERK Kinase Inhibitor with Anti-Myeloma Activity

Discovery of Synergistic Drug Combinations for Colorectal Cancer Driven by Tumor Barcode Derived from Metabolomics “Big Data”

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