&lt;p&gt;Harmine suppresses the proliferation of pancreatic cancer cells and sensitizes pancreatic cancer to gemcitabine treatment&lt;/p&gt;

Wu, Liquan; Zhang, Jiankang; Rao, Mingjun; Zhang, Zuo-yan; Zhu, Huajian; Zhang, Chong

doi:10.2147/ott.s205097

Cited by 36 publications

(26 citation statements)

References 26 publications

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“…The 48-hour treatment with both compounds resulted in an induction of the accumulation of cells in the subG1 phase (apoptotic cells), up to 10% and 15%, respectively (data not shown). As discussed earlier, harmine shows anticancer activity in multiple types of cancer, through various mechanisms, whereby the IC 50 concentrations differed between the cell lines [35,36]. It is interesting to note that, in our hands, treatment of MCF-7 cells with harmine resulted in an order of magnitude lower IC 50 value than reported earlier [37].…”

Section: Cell Cycle Analysissupporting

confidence: 52%

Synthesis and Biological Evaluation of Harmirins, Novel Harmine–Coumarin Hybrids as Potential Anticancer Agents

et al. 2021

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As cancer remains one of the major health burdens worldwide, novel agents, due to the development of resistance, are needed. In this work, we designed and synthesized harmirins, which are hybrid compounds comprising harmine and coumarin scaffolds, evaluated their antiproliferative activity, and conducted cell localization and cell cycle analysis experiments. Harmirins were prepared from the corresponding alkynes and azides under mild reaction conditions using Cu(I) catalyzed azide–alkyne cycloaddition, leading to the formation of the 1H-1,2,3-triazole ring. Antiproliferative activity of harmirins was evaluated in vitro against four human cancer cell lines (MCF-7, HCT116, SW620, and HepG2) and one human non-cancer cell line (HEK293T). The most pronounced activities were exerted against MCF-7 and HCT116 cell lines (IC50 in the single-digit micromolar range), while the most selective harmirins were 5b and 12b, substituted at C-3 and O-7 of the β-carboline core and bearing methyl substituent at position 6 of the coumarin ring (SIs > 7.2). Further experiments demonstrated that harmirin 12b is localized exclusively in the cytoplasm. In addition, it induced a strong G1 arrest and reduced the percentage of cells in the S phase, suggesting that it might exert its antiproliferative activity through inhibition of DNA synthesis, rather than DNA damage. In conclusion, harmirin 12b is a novel harmine and coumarin hybrid with significant antiproliferative activity and warrants further evaluation as a potential anticancer agent.

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Section: Cell Cycle Analysissupporting

confidence: 52%

Synthesis and Biological Evaluation of Harmirins, Novel Harmine–Coumarin Hybrids as Potential Anticancer Agents

et al. 2021

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“…28 For example, compared with gemcitabine alone, gemcitabine and harmine combination therapy provides enhanced therapeutic benefit in pancreatic cancer. 29 Consequently, it is of great interest to identify new therapeutic agents to increase the chemosensitivity of gemcitabine and develop novel combination-therapy approaches. Herbal medicines and plant-derived compounds are becoming increasingly important sources of cancer-chemopreventive or adjuvant chemotherapy.…”

Section: Dovepressmentioning

confidence: 99%

<p>Saikosaponin D Inhibits Proliferation and Promotes Apoptosis Through Activation of MKK4–JNK Signaling Pathway in Pancreatic Cancer Cells</p>

Lai

Chen

et al. 2020

OTT

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Introduction: Pancreatic cancer remains one of the most lethal malignancies and has few treatment options. Saikosaponin D (SSD), a major bioactive triterpene saponin isolated from Bupleurum chinense, has been reported to exert cytotoxicity properties toward many cancer cells. However, the effects of SSD on pancreatic cancer have been little scrutinized. Methods: Here, we investigated the effect of SSD on the proliferation and apoptosis of human pancreatic cancer BxPC3 and PANC1 cells and the mouse pancreatic cancer cell line Pan02. Cell viability was determined by MTT assays and cell apoptosis analyzed by DAPI staining and flow cytometry. Expression levels of apoptosis-regulating markers and activity of the MKK4-JNK signaling pathway were determined by Western blotting. The inhibitor SP600125 was applied to confirm the role of the JNK pathway in SSD efficiency. Results: SSD significantly inhibited the proliferation of BxPC3, PANC1, and Pan02 cells in a concentration-and time-dependent manner. Flow-cytometry analysis indicated obvious apoptosis induction after SSD exposure. Furthermore, SSD significantly triggered cleavage of caspase 3 and caspase 9 proteins and increased the expression of FoxO3a. In addition, activity of the MKK4-JNK pathway was dramatically increased after treatment with SSD in BxPC3 cells. SSD obviously stimulated phosphorylation of JNK, cJun, and SEK1/MKK4 proteins within 30 minutes. The addition of SP600125 blocked the activation of SSD on the MKK4-JNK regulatory pathway and reversed the effects of SSD on proliferation inhibition and apoptosis induction in BxPC3 cells. Conclusion: These results revealed that SSD was capable of suppressing tumor growth and promoting apoptosis of pancreatic cancer cells via targeting the MKK4-JNK signaling pathway, indicating the possibility of further developing SSD as a potential therapeutic candidate for pancreatic cancer.

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“…While Mdivi-1, Dynasore, and P110 suppress tumor malignancy, direct inhibition of mitochondrial fission may be toxic to life. DYRK3 may be an upstream regulator of DRP1 and may be a target of chemical inhibitors such as Harmine and GSK-626616, which were proposed as novel and promising cancer treatment strategies [ 48 , 49 ]. Harmine in particular has been used in clinical studies and can penetrate the blood brain barrier, allowing for brain-specific delivery [ 50 ].…”

Section: Discussionmentioning

confidence: 99%

Dual Specificity Kinase DYRK3 Promotes Aggressiveness of Glioblastoma by Altering Mitochondrial Morphology and Function

Kim

Lee

Kang

et al. 2021

IJMS

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Glioblastoma multiforme (GBM) is a malignant primary brain tumor with poor patient prognosis. Although the standard treatment of GBM is surgery followed by chemotherapy and radiotherapy, often a small portion of surviving tumor cells acquire therapeutic resistance and become more aggressive. Recently, altered kinase expression and activity have been shown to determine metabolic flux in tumor cells and metabolic reprogramming has emerged as a tumor progression regulatory mechanism. Here we investigated novel kinase-mediated metabolic alterations that lead to acquired GBM radioresistance and malignancy. We utilized transcriptomic analyses within a radioresistant GBM orthotopic xenograft mouse model that overexpresses the dual specificity tyrosine-phosphorylation-regulated kinase 3 (DYRK3). We find that within GBM cells, radiation exposure induces DYRK3 expression and DYRK3 regulates mammalian target of rapamycin complex 1 (mTORC1) activity through phosphorylation of proline-rich AKT1 substrate 1 (PRAS40). We also find that DYRK3 knockdown inhibits dynamin-related protein 1 (DRP1)-mediated mitochondrial fission, leading to increased oxidative phosphorylation (OXPHOS) and reduced glycolysis. Importantly, enforced DYRK3 downregulation following irradiation significantly impaired GBM cell migration and invasion. Collectively, we suggest DYRK3 suppression may be a novel strategy for preventing GBM malignancy through regulating mitochondrial metabolism.

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<p>Harmine suppresses the proliferation of pancreatic cancer cells and sensitizes pancreatic cancer to gemcitabine treatment</p>

Cited by 36 publications

References 26 publications

Synthesis and Biological Evaluation of Harmirins, Novel Harmine–Coumarin Hybrids as Potential Anticancer Agents

Synthesis and Biological Evaluation of Harmirins, Novel Harmine–Coumarin Hybrids as Potential Anticancer Agents

<p>Saikosaponin D Inhibits Proliferation and Promotes Apoptosis Through Activation of MKK4–JNK Signaling Pathway in Pancreatic Cancer Cells</p>

Dual Specificity Kinase DYRK3 Promotes Aggressiveness of Glioblastoma by Altering Mitochondrial Morphology and Function

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