Bosutinib, an <scp>SRC</scp> inhibitor, induces caspase‐independent cell death associated with permeabilization of lysosomal membranes in melanoma cells

Noguchi, Shunsuke; Shibutani, Shusaku; Fukushima, Kunio; Mori, Takashi; Igase, Masaya; Mizuno, Takuya

doi:10.1111/vco.12312

Cited by 16 publications

(14 citation statements)

References 25 publications

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“…The majority of lysosomes have an acidic luminal pH between 4.7 and 4.9 [10,11] and hence entrap a vast array of prognostic and therapeutic agents, all of which are hydrophobic weakly basic compounds [5] termed lysosomotropic drugs (LDs) [12]. Previous studies have found that LDs display a common denominator: beyond marked sequestration in lysosomes, LDs inflict lysosomal membrane permeabilization (LMP) [13][14][15][16][17]. In this respect, we, as well as others, have shown that multiple compounds that induce membrane permeabilization are typically bona fide membrane fluidizing agents which enhance the passive diffusion rates of lipid-soluble compounds and drugs [18][19][20][21].…”

Section: Introductionmentioning

confidence: 99%

The Lysosomotropic Activity of Hydrophobic Weak Base Drugs is Mediated via Their Intercalation into the Lysosomal Membrane

Stark

Silva

Levin

et al. 2020

Cells

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Lipophilic weak base therapeutic agents, termed lysosomotropic drugs (LDs), undergo marked sequestration and concentration within lysosomes, hence altering lysosomal functions. This lysosomal drug entrapment has been described as luminal drug compartmentalization. Consistent with our recent finding that LDs inflict a pH-dependent membrane fluidization, we herein demonstrate that LDs undergo intercalation and concentration within lysosomal membranes. The latter was revealed experimentally and computationally by (a) confocal microscopy of fluorescent compounds and drugs within lysosomal membranes, and (b) molecular dynamics modeling of the pH-dependent membrane insertion and accumulation of an assortment of LDs, including anticancer drugs. Based on the multiple functions of the lysosome as a central nutrient sensory hub and a degradation center, we discuss the molecular mechanisms underlying the alteration of morphology and impairment of lysosomal functions as consequences of LDs’ intercalation into lysosomes. Our findings bear important implications for drug design, drug induced lysosomal damage, diseases and pertaining therapeutics.

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Section: Introductionmentioning

confidence: 99%

The Lysosomotropic Activity of Hydrophobic Weak Base Drugs is Mediated via Their Intercalation into the Lysosomal Membrane

Stark

Silva

Levin

et al. 2020

Cells

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“…Since lysosomal membrane permeabilization (LMP) is a frequent cause of lysosomal dysfunction, and leads to leakage of cathepsin B and/or cathepsin D from the lysosome into the cytoplasm, resulting in cell death [31,32,33], we determined whether SB365-induced cell death was due to leakage of cathepsins. To this end, cell proliferation was evaluated 72 h after SB365 treatment in the presence or absence of cathepsin inhibitors.…”

Section: Resultsmentioning

confidence: 99%

SB365, Pulsatilla Saponin D Induces Caspase-Independent Cell Death and Augments the Anticancer Effect of Temozolomide in Glioblastoma Multiforme Cells

Hong

Kim

et al. 2019

Molecules

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SB365, a saponin D extracted from the roots of Pulsatilla koreana, has been reported to show cytotoxicity in several cancer cell lines. We investigated the effects of SB365 on U87-MG and T98G glioblastoma multiforme (GBM) cells, and its efficacy in combination with temozolomide for treating GBM. SB365 exerted a cytotoxic effect on GBM cells not by inducing apoptosis, as in other cancer cell lines, but by triggering caspase-independent cell death. Inhibition of autophagic flux and neutralization of the lysosomal pH occurred rapidly after application of SB365, followed by deterioration of mitochondrial membrane potential. A cathepsin B inhibitor and N-acetyl cysteine, an antioxidant, partially recovered cell death induced by SB365. SB365 in combination with temozolomide exerted an additive cytotoxic effect in vitro and in vivo. In conclusion, SB365 inhibits autophagic flux and induces caspase-independent cell death in GBM cells in a manner involving cathepsin B and mainly reactive oxygen species, and its use in combination with temozolomide shows promise for the treatment of GBM.

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“…A phase Ib study using lenvatinib (E7080) in combination with temozolomide for the treatment of advanced melanoma indicated an overall objective response rate of 18.8% (six patients), comprising all partial responses (55). SRC proto-oncogene, non-receptor tyrosine kinase (SRC) is a promising target in the treatment of solid types of cancer, including human melanoma; bosutinib, a SRC inhibitor, which induces cell death via lysosomal membrane permeabilization in melanoma cells, is a promising therapeutic agent for melanoma treatment (56). SRC inhibitor Dasatinib specifically inhibits p53 phosphorylation in melanoma; however, a comprehensive validation is required (57).…”

Section: Discussionmentioning

confidence: 99%

Prognostic genes of melanoma identified by weighted gene co‑expression network analysis and drug repositioning using a network‑based method

Wang

Wei

et al. 2019

Oncol Lett

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Melanoma is one of the most malignant types of skin cancer. However, the efficacy and utility of available drug therapies for melanoma are limited. The objective of the present study was to identify potential genes associated with melanoma progression and to explore approved therapeutic drugs that target these genes. Weighted gene co-expression network analysis was used to construct a gene co-expression network, explore the associations between genes and clinical characteristics and identify potential biomarkers. Gene expression profiles of the GSE65904 dataset were obtained from the Gene Expression Omnibus database. RNA-sequencing data and clinical information associated with melanoma obtained from The Cancer Genome Atlas were used for biomarker validation. A total of 15 modules were identified through average linkage hierarchical clustering. In the two significant modules, three network hub genes associated with melanoma prognosis were identified: C-X-C motif chemokine receptor 4 (CXCR4), interleukin 7 receptor (IL7R) and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit γ (PIK3CG). The receiver operating characteristic curve indicated that the mRNA levels of these genes exhibited excellent prognostic efficiency for primary and metastatic tumor tissues. In addition, the proximity between candidate genes associated with melanoma progression and drug targets obtained from DrugBank was calculated in the protein interaction network, and the top 15 drugs that may be suitable for treating melanoma were identified. In summary, co-expression network analysis led to the selection of CXCR4, IL7R and PIK3CG for further basic and clinical research on melanoma. Utilizing a network-based method, 15 drugs that exhibited potential for the treatment of melanoma were identified.

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Bosutinib, an SRC inhibitor, induces caspase‐independent cell death associated with permeabilization of lysosomal membranes in melanoma cells

Abstract: Our data suggest that Bosu induces the cell death through induction of LMP in melanoma cells and is a promising therapeutic agent for treatment of melanoma in both dogs and humans.

Cited by 16 publications

References 25 publications

The Lysosomotropic Activity of Hydrophobic Weak Base Drugs is Mediated via Their Intercalation into the Lysosomal Membrane

The Lysosomotropic Activity of Hydrophobic Weak Base Drugs is Mediated via Their Intercalation into the Lysosomal Membrane

SB365, Pulsatilla Saponin D Induces Caspase-Independent Cell Death and Augments the Anticancer Effect of Temozolomide in Glioblastoma Multiforme Cells

Prognostic genes of melanoma identified by weighted gene co‑expression network analysis and drug repositioning using a network‑based method

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