Luteolin inhibits the TGF-β signaling pathway to overcome bortezomib resistance in multiple myeloma

Li, Zhenzhen; Wang, Haiqin; Wang, Yanpeng; Ma, Zekang; Hu, Lei; Luo, Sanchuan; Gong, Yanfei; Zhu, Lin; Gong, Han; Xiang, Ruohong; Zhu, Yu; Xie, Yifang; Yang, Chaoying; Peng, Hongling; Liu, Jing; Xiao, Xiaojuan

doi:10.1016/j.canlet.2022.216019

Cited by 9 publications

(7 citation statements)

References 48 publications

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“…29,30 Several studies have indicated that bioactive compounds can overcome BTZ resistance by targeting CSCs through various signaling pathways, such as NF-κB and transforming growth factor beta (TGF-β), and the modulation of ROS. 8,12,22,31 Emerging evidences suggested that IL-33 exerts antitumor effects through various mechanisms, including enhancing antitumor immunity, inhibiting proliferation, and promoting apoptosis of cancer cells. [25][26][27]32,33 A previous study showed that low plasma IL-33 levels are related to advanced staging of MM, 34 indicating that IL-33 may be a favorable prognostic indicator of MM.…”

Section: Discussionmentioning

confidence: 99%

“…BTZ monotherapy induces an increase in CSC properties, and this is an important mechanism behind BTZ resistance in MM 29,30 . Several studies have indicated that bioactive compounds can overcome BTZ resistance by targeting CSCs through various signaling pathways, such as NF‐κB and transforming growth factor beta (TGF‐β), and the modulation of ROS 8,12,22,31 . Emerging evidences suggested that IL‐33 exerts antitumor effects through various mechanisms, including enhancing antitumor immunity, inhibiting proliferation, and promoting apoptosis of cancer cells 25–27,32,33 .…”

Section: Discussionmentioning

confidence: 99%

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Interleukin‐33 increases the sensitivity of multiple myeloma cells to the proteasome inhibitor bortezomib through reactive oxygen species‐mediated inhibition of nuclear factor kappa‐B signal and stemness properties

Shao,

Liu,

Liu

et al. 2024

MedComm

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The proteasome inhibitor bortezomib (BTZ) is the first‐line therapy for multiple myeloma (MM). BTZ resistance largely limits its clinical application in MM. Interleukin‐33 (IL‐33) exerts antitumor effects through various mechanisms, including enhancing antitumor immunity and promoting the apoptosis of cancer cells. Here, the synergistic anti‐MM effect of IL‐33 and BTZ was verified, and the underlying mechanisms were elucidated. Bioinformatic analysis indicated that IL‐33 expression levels were downregulated in MM, and that BTZ‐treated MM patients with high IL‐33 levels had better prognosis than those with low IL‐33 levels. Moreover, the patients with high IL‐33 levels had a better treatment response to BTZ. Further immune analysis suggested that IL‐33 can enhance the anti‐MM immunity. IL‐33 and BTZ synergistically inhibited proliferation and induced apoptosis of MM cells, which was mediated by the excessive accumulation of cellular reactive oxygen species (ROS). Furthermore, increased ROS hindered the nuclear translocation of NF‐κB‐p65, thereby decreasing the transcription of target stemness‐related genes (SOX2, MYC, and OCT3/4). These effects induced by the combination therapy could be reversed by eliminating ROS by N‐acetylcysteine. In conclusion, our results indicated that IL‐33 enhanced the sensitivity of MM to BTZ through ROS‐mediated inhibition of nuclear factor kappa‐B (NF‐κB) signal and stemness properties.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Interleukin‐33 increases the sensitivity of multiple myeloma cells to the proteasome inhibitor bortezomib through reactive oxygen species‐mediated inhibition of nuclear factor kappa‐B signal and stemness properties

Shao,

Liu,

Liu

et al. 2024

MedComm

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“…Fortunately, this adverse situation can be overcome via the mechanism of luteolin-inducing mitochondrial dysfunction, yet the specific mechanism remains elusive (Özerkan, 2023). In addition, valproate, erlotinib, bortezomib, and irinotecan are often applied in combination with luteolin to endow positive significance in tumor treatment (Boeing et al, 2022;Han et al, 2021;Li, Wang, et al, 2023;Powe et al, 2022). Generally cell MCF-7 model (Yang, Zheng, et al, 2021).…”

Section: Combination With Chemotherapeuticsmentioning

confidence: 99%

“…Fortunately, this adverse situation can be overcome via the mechanism of luteolin‐inducing mitochondrial dysfunction, yet the specific mechanism remains elusive (Özerkan, 2023). In addition, valproate, erlotinib, bortezomib, and irinotecan are often applied in combination with luteolin to endow positive significance in tumor treatment (Boeing et al, 2022; Han et al, 2021; Li, Wang, et al, 2023; Powe et al, 2022). Generally speaking, luteolin is currently mainly utilized in combination with chemotherapeutics with various biological mechanisms such as tyrosine kinase inhibitor, DNA synthesis inhibitor, chymotrypsin‐like activity inhibitor for synergy in the treatment of multiple tumors.…”

Section: Combination Therapy Strategiesmentioning

confidence: 99%

Luteolin, a flavone ingredient: Anticancer mechanisms, combined medication strategy, pharmacokinetics, clinical trials, and pharmaceutical researches

Shi,

Chen,

Gong

et al. 2023

Phytotherapy Research

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Current pharmaceutical research is energetically excavating the pharmacotherapeutic role of herb‐derived ingredients in multiple malignancies’ targeting. Luteolin is one of the major phytochemical components that exist in various traditional Chinese medicine or medical herbs. Mounting evidence reveals that this phytoconstituent endows prominent therapeutic actions on diverse malignancies, with the underlying mechanisms, combined medication strategy, and pharmacokinetics elusive. Additionally, the clinical trial and pharmaceutical investigation of luteolin remain to be systematically delineated. The present review aimed to comprehensively summarize the updated information with regard to the anticancer mechanism, combined medication strategies, pharmacokinetics, clinical trials, and pharmaceutical researches of luteolin. The survey corroborates that luteolin executes multiple anticancer effects mainly by dampening proliferation and invasion, spurring apoptosis, intercepting cell cycle, regulating autophagy and immune, inhibiting inflammatory response, inducing ferroptosis, and pyroptosis, as well as epigenetic modification, and so on. Luteolin can be applied in combination with numerous clinical anticarcinogens and natural ingredients to synergistically enhance the therapeutic efficacy of malignancies while reducing adverse reactions. For pharmacokinetics, luteolin has an unfavorable oral bioavailability, it mainly persists in plasma as glucuronides and sulfate‐conjugates after being metabolized, and is regarded as potent inhibitors of OATP1B1 and OATP2B1, which may be messed with the pharmacokinetic interactions of miscellaneous bioactive substances in vivo. Besides, pharmaceutical innovation of luteolin with leading‐edge drug delivery systems such as host–guest complexes, nanoparticles, liposomes, nanoemulsion, microspheres, and hydrogels are beneficial to the exploitation of luteolin‐based products. Moreover, some registered clinical trials on luteolin are being carried out, yet clinical research on anticancer effects should be continuously promoted.

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“…TGF‐β modulates a wide range of cell types that are present in the tumour microenvironment. MM cells are exposed to high levels of TGF‐β secreted from both MM cells and bone marrow stromal cells, leading to further activation of cell growth and survival pathways 19,20 . Overexpression (OE) of PRUNE1 has been observed in several tumours, including lung cancer, breast cancer, medulloblastoma, colorectal liver metastases and hepatocellular carcinoma 21,22 .…”

Section: Introductionmentioning

confidence: 99%

PRUNE1 (located on chromosome 1q21.3) promotes multiple myeloma with 1q21 Gain by enhancing the links between purine and mitochondrion

Xu,

Wang,

et al. 2023

Br J Haematol

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SummaryPatients with multiple myeloma (MM) with chromosome 1q21 Gain (1q21+) are clinically and biologically heterogeneous. 1q21+ in the real world actually reflects the prognosis for gain/amplification of the CKS1B gene. In this study, we found that the copy number of prune exopolyphosphatase 1 (PRUNE1), located on chromosome 1q21.3, could further stratify the prognosis of MM patients with 1q21+. Using selected reaction monitoring/multiple reaction monitoring (SRM/MRM) analysis, liquid chromatography–tandem mass spectrometry (LC–MS/MS), transmission electron microscopy (TEM), confocal fluorescence microscopy, calculation of adenosine triphosphate (ATP), intracellular reactive oxygen species (ROS) and mitochondrial oxygen consumption rates (OCRs), we demonstrated for the first time that PRUNE1 promotes the proliferation and invasion of MM cells by stimulating purine metabolism, purine synthesis enzymes and mitochondrial functions, enhancing links between purinosomes and mitochondria. SOX11 was identified as a transcription factor for PRUNE1. Through integrated analysis of the transcriptome and proteome, CD73 was determined to be the downstream target of PRUNE1. Furthermore, it has been determined that dipyridamole can effectively suppress the proliferation of MM cells with high‐expression levels of PRUNE1 in vitro and in vivo. These findings provide insights into disease‐causing mechanisms and new therapeutic targets for MM patients with 1q21+.

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Luteolin inhibits the TGF-β signaling pathway to overcome bortezomib resistance in multiple myeloma

Cited by 9 publications

References 48 publications

Interleukin‐33 increases the sensitivity of multiple myeloma cells to the proteasome inhibitor bortezomib through reactive oxygen species‐mediated inhibition of nuclear factor kappa‐B signal and stemness properties

Interleukin‐33 increases the sensitivity of multiple myeloma cells to the proteasome inhibitor bortezomib through reactive oxygen species‐mediated inhibition of nuclear factor kappa‐B signal and stemness properties

Luteolin, a flavone ingredient: Anticancer mechanisms, combined medication strategy, pharmacokinetics, clinical trials, and pharmaceutical researches

PRUNE1 (located on chromosome 1q21.3) promotes multiple myeloma with 1q21 Gain by enhancing the links between purine and mitochondrion

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