Ridaifen-F conjugated with cell-penetrating peptides inhibits intracellular proteasome activities and induces drug-resistant cell death

Tanaka, Makoto; Zhu, Yongwei; Shionyu, Masafumi; Ota, Nozomi; Shibata, N.; Watanabe, Chihiro; Mizusawa, Akihito; Sasaki, Ryuzo; Mizukami, Tamio; Shiina, Isamu; Hasegawa, Makoto

doi:10.1016/j.ejmech.2018.01.045

Cited by 9 publications

(7 citation statements)

References 54 publications

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“…[19,20] RID analogues work via noncovalent and nonpeptidic proteasome inhibition, and therefore are promising candidates in TNBC and other cancer types. [20][21][22] Herein we report twenty-five flexible triphenylethylene analogues. Compounds are designed to bypass CYP2D6 metabolism and are alternatively metabolized to the more potent hydroxy metabolite via esterases.…”

Section: Introductionmentioning

confidence: 99%

Flexible Etherified and Esterified Triphenylethylene Derivatives and Their Evaluation on ER‐positive and Triple‐Negative Breast Cancer Cell Lines

et al. 2022

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Tamoxifen (TAM) is a selective estrogen receptor modulator (SERM) with potential clinical benefits for all stages of breast cancer. TAM is primarily metabolized to more potent metabolites via polymorphic CYP2D6. This affects the clinical outcome of TAM treatment. Herein we report novel TAM analogues that can avoid metabolism via CYP2D6. The novel analogues bear a flexible skeleton. Compounds have either an ester group on ring C or homodiaminoalkoxy groups on rings B and C.propenyl]phenol) was found to be ten-fold more potent than TAM on MCF-7 cells (GI 50 = 0.15 μM). It showed fivefold greater inhibitory activity on MDA-MB-231 cells than TAM (GI 50 = 1.71 μM). Compound 13 (4-{3,3-bis-[4-(3dimethylaminopropoxy)phenyl]-2-methylallyl}methoxybenzene) was the most potent among the homodiaminoalkoxy derivatives (GI 50 = 0.44) on both MCF-7 and MDA-MB-231 cell lines, respectively. Furthermore, the COMPARE algorithm suggested that it has different molecular targets from those of some other reported anticancer drugs.

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Section: Introductionmentioning

confidence: 99%

Flexible Etherified and Esterified Triphenylethylene Derivatives and Their Evaluation on ER‐positive and Triple‐Negative Breast Cancer Cell Lines

et al. 2022

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“…Poor permeation into cells may be a widespread mechanism that underlies modest performance of a drug. We have shown that conjugation of a proteasome inhibitor (ridaifen-F) to a cell-penetrating peptide markedly elevates the inhibition of cellular proteasome through accelerated uptake 61 , suggesting modification point of ryuvidine. Intracellular modifications would also impair drug efficacy.…”

Section: Discussionmentioning

confidence: 98%

Identification of ryuvidine as a KDM5A inhibitor

Mitsui

Yoshida

Shinoda

et al. 2019

Sci Rep

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KDM5 family members (A, B, C and D) that demethylate H3K4me3 have been shown to be involved in human cancers. Here we performed screening for KDM5A inhibitors from chemical libraries using the AlphaScreen method and identified a battery of screening hits that inhibited recombinant KDM5A. These compounds were further subjected to cell-based screening using a reporter gene that responded to KDM5A inhibition and 6 compounds were obtained as candidate inhibitors. When further confirmation of their inhibition activity on cellular KDM5A was made by immunostaining H3K4me3 in KDM5A-overexpressing cells, ryuvidine clearly repressed H3K4me3 demethylation. Ryuvidine prevented generation of gefitinib-tolerant human small-cell lung cancer PC9 cells and also inhibited the growth of the drug-tolerant cells at concentrations that did not affect the growth of parental PC9 cells. Ryuvidine inhibited not only KDM5A but also recombinant KDM5B and C; KDM5B was the most sensitive to the inhibitor. These results warrant that ryuvidine may serve as a lead compound for KDM5 targeted therapeutics.

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“…Secondly, the polypeptide fragment promoted penetration of the conjugate into cells and increased intracellular RID‐F concentration to a level sufficient to inhibit the proteasome. The results denoted that the R8‐containing conjugate of RID‐F inhibited the 26S proteasome and intracellular proteasome in KMS‐11 cells 178 . Reports have evidenced that the use of CPP for the delivery of chemotherapy may be therapeutically valuable due to enhanced pharmaceutical features.…”

Section: Cpps and Anti‐cancer Cargoes Deliverymentioning

confidence: 93%

“…The results denoted that the R8-containing conjugate of RID-F inhibited the 26S proteasome and intracellular proteasome in KMS-11 cells. 178 Reports have evidenced that the use of CPP for the delivery of chemotherapy may be therapeutically valuable due to enhanced pharmaceutical features.…”

Section: Hormone Therapy Agentsmentioning

confidence: 99%

The role of cell‐penetrating peptides in potential anti‐cancer therapy

Zhou

Zou

Cheng

et al. 2022

Clinical & Translational Med

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Due to the complex physiological structure, microenvironment and multiple physiological barriers, traditional anti‐cancer drugs are severely restricted from reaching the tumour site. Cell‐penetrating peptides (CPPs) are typically made up of 5–30 amino acids, and can be utilised as molecular transporters to facilitate the passage of therapeutic drugs across physiological barriers. Up to now, CPPs have widely been used in many anti‐cancer treatment strategies, serving as an excellent potential choice for oncology treatment. However, their drawbacks, such as the lack of cell specificity, short duration of action, poor stability in vivo, compatibility problems (i.e. immunogenicity), poor therapeutic efficacy and formation of unwanted metabolites, have limited their further application in cancer treatment. The cellular uptake mechanisms of CPPs involve mainly endocytosis and direct penetration, but still remain highly controversial in academia. The CPPs‐based drug delivery strategy could be improved by clever design or chemical modifications to develop the next‐generation CPPs with enhanced cell penetration capability, stability and selectivity. In addition, some recent advances in targeted cell penetration that involve CPPs provide some new ideas to optimise CPPs.

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Ridaifen-F conjugated with cell-penetrating peptides inhibits intracellular proteasome activities and induces drug-resistant cell death

Cited by 9 publications

References 54 publications

Flexible Etherified and Esterified Triphenylethylene Derivatives and Their Evaluation on ER‐positive and Triple‐Negative Breast Cancer Cell Lines

Flexible Etherified and Esterified Triphenylethylene Derivatives and Their Evaluation on ER‐positive and Triple‐Negative Breast Cancer Cell Lines

Identification of ryuvidine as a KDM5A inhibitor

The role of cell‐penetrating peptides in potential anti‐cancer therapy

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