Homoharringtonine Combined with the Heat Shock Protein 90 Inhibitor IPI504 in the Treatment of FLT3-ITD Acute Myeloid Leukemia

Wu, Zhaoxing; Zhuang, Haifeng; Yu, Qiuming; Zhang, Xuzhao; Jiang, Xudong; Lu, Xuesong; Xu, Ying; Yang, Linlin; Wu, Bowen; Ma, An; Zhang, Lei; Xiao, Xibin; Liang, Yun; Gao, Ruilan; Shen, Jianping; Xu, Rongzhen

doi:10.1016/j.tranon.2019.02.016

Cited by 16 publications

(10 citation statements)

References 36 publications

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“…HHT had synergistic effects with a Heat Shock Protein 90 inhibitor on FLT3-ITD+ AML models [111], with etoposide on primary and AML cell lines [112]. HHT synergized with oridonin on t(8; 21) AML cells by downregulating signaling via c-KIT and decreasing levels of the multi drug resistance proteins MRD1 and MRP1, in order to increase the effective concentration of oridonin [113].…”

Section: Combining Ribosome Inhibition With Classical Chemotherapeutimentioning

confidence: 99%

Targeting the Human 80S Ribosome in Cancer: From Structure to Function and Drug Design for Innovative Adjuvant Therapeutic Strategies

Gilles

Fréchin

Natchiar

et al. 2020

Cells

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The human 80S ribosome is the cellular nucleoprotein nanomachine in charge of protein synthesis that is profoundly affected during cancer transformation by oncogenic proteins and provides cancerous proliferating cells with proteins and therefore biomass. Indeed, cancer is associated with an increase in ribosome biogenesis and mutations in several ribosomal proteins genes are found in ribosomopathies, which are congenital diseases that display an elevated risk of cancer. Ribosomes and their biogenesis therefore represent attractive anti-cancer targets and several strategies are being developed to identify efficient and specific drugs. Homoharringtonine (HHT) is the only direct ribosome inhibitor currently used in clinics for cancer treatments, although many classical chemotherapeutic drugs also appear to impact on protein synthesis. Here we review the role of the human ribosome as a medical target in cancer, and how functional and structural analysis combined with chemical synthesis of new inhibitors can synergize. The possible existence of oncoribosomes is also discussed. The emerging idea is that targeting the human ribosome could not only allow the interference with cancer cell addiction towards protein synthesis and possibly induce their death but may also be highly valuable to decrease the levels of oncogenic proteins that display a high turnover rate (MYC, MCL1). Cryo-electron microscopy (cryo-EM) is an advanced method that allows the visualization of human ribosome complexes with factors and bound inhibitors to improve our understanding of their functioning mechanisms mode. Cryo-EM structures could greatly assist the foundation phase of a novel drug-design strategy. One goal would be to identify new specific and active molecules targeting the ribosome in cancer such as derivatives of cycloheximide, a well-known ribosome inhibitor.

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Section: Combining Ribosome Inhibition With Classical Chemotherapeutimentioning

confidence: 99%

Targeting the Human 80S Ribosome in Cancer: From Structure to Function and Drug Design for Innovative Adjuvant Therapeutic Strategies

Gilles

Fréchin

Natchiar

et al. 2020

Cells

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“…In recent years, FLT3 has been developed as an important marker in different haematological malignancies [121]. Homoharringtonine (HHT), an alkaloid isolated from Cephalotaxus species, was able to suppress the expression of FLT3/p-FLT3 and inhibit the growth of human AML MV4-11 and MOLM-13 cells in nanomolar level [122]. A benzylamine alkaloid, 2-acetyl-benzylamin, isolated from Adhatoda vasica, displayed potent anticancer effect by down-regulation of JAK2 and FLT3.…”

Section: Discussionmentioning

confidence: 99%

Protein kinases as therapeutic targets to develop anticancer drugs with natural alkaloids

Wang

et al. 2021

Front. Biosci. (Landmark Ed)

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Backgroud: Protein kinases play an important role in cell proliferation, differentiation, mobility and cell cycle arrest etc. These enzymes act as important targets in developing anticancer agents. Over the years, a large number of protein kinase inhibitors have been discovered and developed as anticancer agents for the treatment of cancers clinically. However, the drug-resiatance and offtargeting limit their effeciancy for the treatment of human cancer. Materials and methods: Alkaloids are an important class of natural products with broad spectrum biological activities. In the past decades, numerus alkaloids with significant anticancer activity by inhibiting protein kinases were identified. In the present mini-review, we will present the key enzymes including mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) and janus-activated kinases/signal transducer and activator of transcription (JAK/STAT) targeted by alkaloids and highlight the special sites targeted by alkaloids on protein kinases and/or reversing drug resistance. Additionally, the challenge and prospect of developing alkaloids as new anticancer agents are also discussed. Conclusion: Alkaloids suppressed tumor growth through targeting different signaling pathways mediated by protein kinases of cancer cells. It is conceivable that novel alkaloids anticancer agents with promising clinical value will be developed in the future.

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“…Elevated ROS generation in *etoposide-treated AML cells and exhibited synergistic cytotoxicity [212]. Combined treatment with HSP90 inhibitor provides an alternative way for the treatment of FLT3-ITD positive AML [213]. FDA approved for treatment of patients with CML resistant or intolerant to tyrosine kinase inhibitors (TKI) [214].…”

Section: Blood and Bone Marrow Cancer (Leukemia)mentioning

confidence: 99%

Complementary and Alternative Treatments for Cancer Prevention and Cure (Part 1)

Mohiuddin¹

2019

JECT

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Many lay people along with some so called "key opinion leaders" have a common slogan "There's no answer for cancer". Again, mistake delays proper treatment and make situation worse, more often. Compliance is crucial to obtain optimal health outcomes, such as cure or improvement in QoL. Patients may delay treatment or fail to seek care because of high out-of-pocket expenditures. Despite phenomenal development, conventional therapy falls short in cancer management. There are two major hurdles in anticancer drug development: dose-limiting toxic side effects that reduce either drug effectiveness or the QoL of patients and complicated drug development processes that are costly and time consuming. Cancer patients are increasingly seeking out alternative medicine and might be reluctant to disclose its use to their oncology treatment physicians. But there is limited available information on patterns of utilization and efficacy of alternative medicine for patients with cancer. As adjuvant therapy, many traditional medicines shown efficacy against brain, head and neck, skin, breast, liver, pancreas, kidney, bladder, prostate, colon and blood cancers. The literature reviews non-pharmacological interventions used against cancer, published trials, systematic reviews and meta-analyses.

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Homoharringtonine Combined with the Heat Shock Protein 90 Inhibitor IPI504 in the Treatment of FLT3-ITD Acute Myeloid Leukemia

Cited by 16 publications

References 36 publications

Targeting the Human 80S Ribosome in Cancer: From Structure to Function and Drug Design for Innovative Adjuvant Therapeutic Strategies

Targeting the Human 80S Ribosome in Cancer: From Structure to Function and Drug Design for Innovative Adjuvant Therapeutic Strategies

Protein kinases as therapeutic targets to develop anticancer drugs with natural alkaloids

Complementary and Alternative Treatments for Cancer Prevention and Cure (Part 1)

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