Lysosome Inhibitors Enhance the Chemotherapeutic Activity of Doxorubicin in HepG2 Cells

Li, Yuyin; Sun, Yuejun; Jing, Lifang; Wang, Jianjun; Yan, Yali; Feng, Yajuan; Zhang, Yueying; Liu, Zhenxing; Ma, Long; Diao, Aipo

doi:10.1159/000448802

Cited by 17 publications

(9 citation statements)

References 28 publications

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“…This is in agreement with a recent study that has shown that supplementation of Dox with lysosome inhibitors such as bafilomycin A1 and chloroquine provided a more efficient anticancer effect in hepatic cancer cells by increasing lysosomal membrane permeability. 51 International Journal of Nanomedicine downloaded from https://www.dovepress.com/ by 44.224.250.200…”

Section: Discussionmentioning

confidence: 99%

Nitric oxide-releasing nanoparticles improve doxorubicin anticancer activity

Alimoradi¹,

Greish²,

Barzegar-Fallah³

et al. 2018

IJN

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PurposeAnticancer drug delivery systems are often limited by hurdles, such as off-target distribution, slow cellular internalization, limited lysosomal escape, and drug resistance. To overcome these limitations, we have developed a stable nitric oxide (NO)-releasing nanoparticle (polystyrene-maleic acid [SMA]-tert-dodecane S-nitrosothiol [tDodSNO]) with the aim of enhancing the anticancer properties of doxorubicin (Dox) and a Dox-loaded nanoparticle (SMA-Dox) carrier.Materials and methodsEffects of SMA-tDodSNO and/or in combination with Dox or SMA-Dox on cell viability, apoptosis, mitochondrial membrane potential, lysosomal membrane permeability, tumor tissue, and tumor growth were studied using in vitro and in vivo model of triple-negative breast cancer (TNBC). In addition, the concentrations of SMA-Dox and Dox in combination with SMA-tDodSNO were measured in cells and tumor tissues.ResultsCombination of SMA-tDodSNO and Dox synergistically decreased cell viability and induced apoptosis in 4T1 (TNBC cells). Incubation of 4T1 cells with SMA-tDodSNO (40 µM) significantly enhanced the cellular uptake of SMA-Dox and increased Dox concentration in the cells resulting in a twofold increase (P<0.001). Lysosomal membrane integrity, evaluated by acridine orange (AO) staining, was impaired by 40 µM SMA-tDodSNO (P<0.05 vs control) and when combined with SMA-Dox, this effect was significantly potentiated (P<0.001 vs SMA-Dox). Subcutaneous administration of SMA-tDodSNO (1 mg/kg) to xenografted mice bearing 4T1 cells showed that SMA-tDodSNO alone caused a twofold decrease in the tumor size compared to the control group. SMA-tDodSNO in combination with SMA-Dox resulted in a statistically significant 4.7-fold reduction in the tumor volume (P<0.001 vs control), without causing significant toxicity as monitored through body weight loss.ConclusionTaken together, these results suggest that SMA-tDodSNO can be used as a successful strategy to increase the efficacy of Dox and SMA-Dox in a model of TNBC.

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Section: Discussionmentioning

confidence: 99%

Nitric oxide-releasing nanoparticles improve doxorubicin anticancer activity

Alimoradi¹,

Greish²,

Barzegar-Fallah³

et al. 2018

IJN

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“…For instance, some have resorted to the use of a so-called "chemosensitizer," such as chloroquine, that elevates the intra-lysosomal pH prior to doxorubicin administration [125]. In addition to serving as a lysosomal alkalinizing agent, chloroquine has also been shown to enhance endogenous nitric oxide production, which can further inhibit P-glycoprotein activity, favoring cytoplasmic localization of doxorubicin, thereby promoting its cytotoxic effects in hepatic cancer cells [126,127]. An alternative strategy to induce LMP is photodynamic therapy (PDT), where lights and a photosensitizer react in the presence of oxygen to form the cytotoxic singlet oxygen [128].…”

Section: Novel Therapeutic Strategies For Lysosome-mediated Chemoresimentioning

confidence: 99%

Getting Lost in the Cell–Lysosomal Entrapment of Chemotherapeutics

Zhai

Hiani

2020

Cancers

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Despite extensive research, resistance to chemotherapy still poses a major obstacle in clinical oncology. An exciting strategy to circumvent chemoresistance involves the identification and subsequent disruption of cellular processes that are aberrantly altered in oncogenic states. Upon chemotherapeutic challenges, lysosomes are deemed to be essential mediators that enable cellular adaptation to stress conditions. Therefore, lysosomes potentially hold the key to disarming the fundamental mechanisms of chemoresistance. This review explores modes of action of classical chemotherapeutic agents, adaptive response of the lysosomes to cell stress, and presents physiological and pharmacological insights pertaining to drug compartmentalization, sequestration, and extracellular clearance through the lens of lysosomes.

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“…One study administered chloroquine to mice and inhibited lysosomal function by raising the lysosomal pH [ 79 ] . A different study found that chloroquine potentiates the cytotoxic effects of doxorubicin in liver carcinoma cells [ 80 ] . Similarly, treatment of lysosomes in resistant cells with monensin, bafilomycin A1, or concanamycin A was sufficient to change the distribution of adriamycin to mimic that of drug-sensitive cells [ 47 ] .…”

Section: Approaches To Reverse Lysosomal Sequestrationmentioning

confidence: 99%

Influence of lysosomal sequestration on multidrug resistance in cancer cells

Halaby¹

2019

CDR

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Chemotherapy remains a primary treatment modality for various malignancies. However, resistance to chemotherapeutic drugs is a major obstacle to curative cancer therapy. Lysosomes are acidic organelles that participate in cellular digestion. However, there is rising interest in lysosomes because of their involvement with cancer. For example, extracellular secretion of lysosomal enzymes promote tumorigenesis; cytosolic leakage of lysosomal hydrolases promote apoptosis; and weak chemotherapeutic bases diffuse across the lysosomal membrane and become entrapped in lysosomes in their cationic state. Lysosomal drug sequestration lowers the cytotoxic potential of chemotherapeutics, reduces drug availability to sites of action, and contributes to cancer resistance. This review examines various mechanisms of lysosomal drug sequestration and their consequences on cancer multidrug resistance. Strategies for overcoming drug resistance by exploiting lysosomes as subcellular targets to reverse drug sequestration and drug resistance are also discussed.

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Lysosome Inhibitors Enhance the Chemotherapeutic Activity of Doxorubicin in HepG2 Cells

Cited by 17 publications

References 28 publications

Nitric oxide-releasing nanoparticles improve doxorubicin anticancer activity

Nitric oxide-releasing nanoparticles improve doxorubicin anticancer activity

Getting Lost in the Cell–Lysosomal Entrapment of Chemotherapeutics

Influence of lysosomal sequestration on multidrug resistance in cancer cells

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