A novel hydrogen sulfide-releasing donor, HA-ADT, suppresses the growth of human breast cancer cells through inhibiting the PI3K/AKT/mTOR and Ras/Raf/MEK/ERK signaling pathways

Dong, Qian; Yang, Bo; Han, Ju-Guo; Zhang, Mengmeng; Liu, Wei; Zhang, Xin; Yu, Hongxiang; Liu, Zhengguo; Zhang, Shihui; Li, Tao; Wu, Dongdong; Ji, Xin‐Ying; Duan, Shaofeng

doi:10.1016/j.canlet.2019.04.031

Cited by 78 publications

(66 citation statements)

References 56 publications

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“…no significance. Raf/MEK/ERK pathways to repress BC cell proliferation, viability, migration, and invasion 24 . GPNMB triggers the PI3K/AKT/mTOR pathway and β-catenin activity to augment BC initiation and growth 25 .…”

Section: Discussionmentioning

confidence: 99%

M2 macrophage-induced lncRNA PCAT6 facilitates tumorigenesis and angiogenesis of triple-negative breast cancer through modulation of VEGFR2

et al. 2020

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As a common female malignancy, triple-negative breast cancer (TNBC) is the most malignant subtype of breast cancers (BC). This study further studied the role of long noncoding RNA (lncRNA) prostate cancer-associated transcript 6 (PCAT6) in TNBC. Functional assays, including EdU, wound healing, transwell, and immunofluorescence staining, revealed the effect of PCAT6 on cell proliferation, migration, and EMT process. The tube-formation assay disclosed the function of PCAT6 on angiogenesis. In vivo assays were also established to explore the impact of PCAT6 on tumor growth and microangiogenesis. The results revealed that PCAT6 boosted TNBC cell proliferation, migration, and angiogenesis both in vitro and in vivo. Then, this study unveiled that M2 macrophage secreted VEGF to stimulate the upregulation of PCAT6, thus promoting angiogenesis in TNBC. Next, through bioinformatics analysis and mechanism assays, we identified that PCAT6 positively regulated VEGFR2 expression via ceRNA pattern and then participated in VEGFR/AKT/mTOR signaling pathway to accelerate angiogenesis. Moreover, PCAT6 bound USP14, a deubiquitinase, to induce the deubiquitination of VEGFR2. On the whole, M2 macrophage-induced upregulation of PCAT6 facilitates TNBC tumorigenesis through modulation of VEGFR2 expression via ceRNA and deubiquitination patterns.

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Section: Discussionmentioning

confidence: 99%

M2 macrophage-induced lncRNA PCAT6 facilitates tumorigenesis and angiogenesis of triple-negative breast cancer through modulation of VEGFR2

et al. 2020

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“…ST) and cystathionine gamma-lyase (CTH/CSE) enzymes [6,8,9]. H 2 S plays a vital role in the establishment and progression of multiple health disorders ranging from non-cancerous [10,11] to cancerous [12,13]. In cancer, H 2 S participates in both the suppression [12,[14][15][16][17] and progression of the disease [13,18].…”

Section: Ivyspring International Publishermentioning

confidence: 99%

“…Therefore, the impact of the activation of the above transporters by H2S donors in cancer should be further examined to clarify the mechanism and the subsequent responses. Besides, H 2 S can also interact with insulin receptors and toll-like receptors 4 (TLR4), resulting in the inhibition of phosphoinositide 3-kinase (PI3K)/AKT/mTOR [12], nuclear factor-kappa B (NF-кB) [54] and signal transducer and activator of transcription-3 (STAT-3) [55] pathways together with their corresponding cellular responses.…”

Section: Mechanisms Involved In H 2 S-mediated Cancer Modulationmentioning

confidence: 99%

“…Likewise, DADS treatment suppresses cancer progression by facilitating DNA damage [120] and inhibiting PI3K/AKT/mTOR [142,143] and NF-кB pathways [32]. In addition, compared to NaHS and GYY4137 treatments, breast cancer cells show extremely high apoptotic index when administered with HA-ADT (a conjugate formed with hyaluronic acid (HA) and ADT-OH) [12]. The extracellular acidic microenvironment is the key feature that differentiates cancer cells from non-cancer cells [158].…”

Section: H 2 S Donor Induces Apoptosismentioning

confidence: 99%

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Role of hydrogen sulfide donors in cancer development and progression

et al. 2021

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In recent years, a vast number of potential cancer therapeutic targets have emerged. However, developing efficient and effective drugs for the targets is of major concern. Hydrogen sulfide (H2S), one of the three known gasotransmitters, is involved in the regulation of various cellular activities such as autophagy, apoptosis, migration, and proliferation. Low production of H2S has been identified in numerous cancer types. Treating cancer cells with H2S donors is the common experimental technique used to improve H2S levels; however, the outcome depends on the concentration/dose, time, cell type, and sometimes the drug used. Both natural and synthesized donors are available for this purpose, although their effects vary independently ranging from strong cancer suppressors to promoters. Nonetheless, numerous signaling pathways have been reported to be altered following the treatments with H2S donors which suggest their potential in cancer treatment. This review will analyze the potential of H2S donors in cancer therapy by summarizing key cellular processes and mechanisms involved.

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“…Improvements in the detection and treatment of breast cancer have led to better prognosis and survival, with a 5year survival rate of nearly 90% 1,2 . However, breast cancer is still one of the most frequent malignant diseases in women worldwide and the second leading cause of mortality in females 1,3,4 . Moreover, there is still no effective treatment strategy for advanced breast cancer that has metastasized 3,5 .…”

Section: Introductionmentioning

confidence: 99%

A novel 4-aminoquinazoline derivative, DHW-208, suppresses the growth of human breast cancer cells by targeting the PI3K/AKT/mTOR pathway

et al. 2020

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Breast cancer is one of the most frequent cancers among women worldwide. However, there is still no effective therapeutic strategy for advanced breast cancer that has metastasized. Aberrant activation of the PI3K/AKT/mTOR pathway is an essential step for the growth of human breast cancers. In our previous study, we designed and synthesized DHW-208 (2,4-difluoro-N-(5-(4-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)quinazolin-6-yl)-2methoxypyridin-3-yl)benzenesulfonamide) as a novel pan-PI3K inhibitor. This study aimed to assess the therapeutic efficacy of DHW-208 in breast cancer and investigate its underlying mechanism. We found that DHW-208 inhibited the growth, proliferation, migration, and invasion of breast cancer cells. Moreover, DHW-208 induced breast cancer cell apoptosis via the mitochondrial pathway and induced G0/G1 cell-cycle arrest. In vitro results show that DHW-208 is a dual inhibitor of PI3K and mTOR, and suppress the growth of human breast cancer cells by targeting the PI3K/AKT/ mTOR pathway. Consistent with the in vitro results, in vivo studies demonstrated that DHW-208 elicits an antitumor effect by inhibiting the PI3K/AKT/mTOR-signaling pathway with a high degree of safety in breast cancer. Above all, we report for the first time that DHW-208 suppressed the growth of human breast cancer cells by inhibiting the PI3K/AKT/ mTOR-signaling pathway both in vivo and in vitro. Our study may provide evidence for the use of DHW-208 as an effective, novel therapeutic candidate for the treatment of human breast cancers in clinical trials.

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A novel hydrogen sulfide-releasing donor, HA-ADT, suppresses the growth of human breast cancer cells through inhibiting the PI3K/AKT/mTOR and Ras/Raf/MEK/ERK signaling pathways

Cited by 78 publications

References 56 publications

M2 macrophage-induced lncRNA PCAT6 facilitates tumorigenesis and angiogenesis of triple-negative breast cancer through modulation of VEGFR2

M2 macrophage-induced lncRNA PCAT6 facilitates tumorigenesis and angiogenesis of triple-negative breast cancer through modulation of VEGFR2

Role of hydrogen sulfide donors in cancer development and progression

A novel 4-aminoquinazoline derivative, DHW-208, suppresses the growth of human breast cancer cells by targeting the PI3K/AKT/mTOR pathway

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