Effect of lysosomotropic molecules on cellular homeostasis

Kuzu, Omer F.; Toprak, Mesut; Noory, Mohammad A.; Robertson, Gavin P.

doi:10.1016/j.phrs.2016.12.021

Cited by 63 publications

(73 citation statements)

References 80 publications

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“…Nanolipolee‐007 significantly induced intracellular cholesterol levels in both circulating and adherent C8161.Cl9‐vGFP (Figure c) and UACC 903M‐GFP (Figure d) cell lines compared to controls, while cotreatment with β‐cyclodextrin reversed the effect. This result suggested that cholesterol transport was inhibited in CTCs following Nanolipolee‐007 treatment and that it could be reversed using β‐cyclodextrin as reported in the literature (Gowda et al., ; Kuzu et al., , , ).…”

Section: Resultssupporting

confidence: 65%

“…β‐Cyclodextrin was premixed with melanoma cells to counteract Nanolipolee‐007, thereby demonstrating the involvement of cholesterol transport inhibition in mediating this process. Thus, leelamine killed circulating melanoma cells through a process that could be reversed using β‐cyclodextrin, which based on the literature, could be due to inhibition of cholesterol transport (Gowda et al., ; Kuzu, Toprak, Noory, & Robertson, ; Kuzu et al., , ).…”

Section: Resultsmentioning

confidence: 99%

“…Inhibition of cholesterol transport makes cholesterol unavailable to cancer cells causing shut down of cellular signaling pathways on which the cancer cell is reliant for cell survival (Gowda et al., ; Kuzu et al., , , ). Two major signaling cascades promoting melanoma development, AKT and STAT3, were inhibited by leelamine in adherent UACC 903 cells after 3–24 hr of treatment (Gowda, Madhunapantula, Kuzu, et al., ; Gowda, Madhunapantula, Sharma, et al., ; Kuzu et al., ).…”

Section: Resultsmentioning

confidence: 99%

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Targeting cholesterol transport in circulating melanoma cells to inhibit metastasis

Chen

Gowda

Newswanger

et al. 2017

Pigment Cell Melanoma Res

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Despite recent breakthroughs in targeted- and immune-based therapies, rapid development of drug resistance remains a hurdle for the long-term treatment of patients with melanoma. Targeting metastatically spreading circulating tumor cells (CTCs) may provide an additional approach to manage melanoma. This study investigates whether targeting cholesterol transport in melanoma CTCs can retard metastasis development. Nanolipolee-007, the liposomal form of leelamine, reduced melanoma metastasis in both a novel in vitro flow system mimicking the circulating system and in experimental as well as spontaneous animal metastasis models, irrespective of the BRAF mutational status of the CTCs. Leelamine led to cholesterol trapping in lysosomes, which subsequently shut down receptor-mediated endocytosis, endosome trafficking, and inhibited the major oncogenic signaling cascades important for survival such as the AKT pathway. As pAKT is important in CTC survival, inhibition by targeting cholesterol metabolism led to apoptosis, suggesting this approach might be particularly effective for those CTCs having high levels of pAKT to aid survival in the circulation system.

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Section: Resultssupporting

confidence: 65%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Targeting cholesterol transport in circulating melanoma cells to inhibit metastasis

Chen

Gowda

Newswanger

et al. 2017

Pigment Cell Melanoma Res

Self Cite

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“…Morphologically, TFEB knockdown induced an enlargement of lysosomes and endosomes in squamous carcinomas. In general, inhibition of lysosomes by pharmacological inhibitors or genetic prevention causes an enlargement of lysosomes and endosomes (Endo, Furuta, & Nishino, ; Kuzu, Toprak, Noory, & Robertson, ). This phenotype is known as “vacuolation.” It should be noted that the vacuolation by lysosomal inhibition affects peripheral organelles.…”

Section: Discussionmentioning

confidence: 99%

Transcription factor EB influences invasion and migration in oral squamous cell carcinomas

et al. 2018

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“…3C), which was in contrast with the cell viability data. We hypothesized that the pre-treatment with Cur@ANPs did not lead to efficient cytotoxicity because Cur aggregated and remained entrapped in the lysosomes as soon as it was released from the NPs due to its weak-base nature (lysosomotropism) (Kuzu et al 2017). In order to validate this hypothesis, we assessed the trafficking profile of Cur in cells treated with Cur/Dox@ANPs for 3 h and in cells pre-treated with Cur@ANPs for 1.5 h and then exposed to Dox@ANPs for an additional 1.5 h by means of confocal laser scanning microscopy (CLSM) (Burger et al 2015).…”

Section: Introductionmentioning

confidence: 99%

Co-encapsulation of curcumin and doxorubicin in albumin nanoparticles blocks the adaptive treatment tolerance of cancer cells

et al. 2019

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The adaptive treatment tolerance (ATT) of cancer cells is the main encumbrance to cancer chemotherapy. A potential solution to this problem is to treat cancer cells with multiple drugs using nanoparticles (NPs).In this study, we tested the co-administration of curcumin (Cur) and doxorubicin (Dox) to MCF-7 resistant breast cancer cells to block the ATTand elicit efficient cell killing. Drugs were co-administered to cells both sequentially and simultaneously. Sequential drug co-administration was carried out by pre-treating the cells with albumin nanoparticles (ANPs) loaded with Cur (Cur@ANPs) followed by treatment with Dox-loaded ANPs (Dox@ANPs). Simultaneous drug co-administration was carried out by treating the cells with ANPs loaded with both the drugs (Cur/Dox@ANPs). We found that the simultaneous drug co-administration led to a greater intra-cellular accumulation of Dox and cell killing with respect to the sequential drug co-administration. However, the simultaneous drug co-administration led to a lower intracellular accumulation of Cur with respect to the sequential drug co-administration. We showed that this result was due to the aggregation and entrapment of Cur in the lysosomes as soon as it was released from Cur@ANPs, a phenomenon called lysosomotropism. In contrast, the simultaneous release of Dox and Cur from Cur/Dox@ANPs into the lysosomes led to lysosomal pH elevation, which, in turn, avoided Cur aggregation, led to lysosome swelling and drug release in the cytosol, and finally provoked efficient cell killing. Our study shed the light on the molecular processes driving the therapeutic effects of anti-cancer drugs co-administered to cancer cells in different manners. Biophysics ReportsRESULTS AND DISCUSSION Preparation and characterization of albumin nanoparticles loaded with Cur and/or Dox Bovine serum albumin (BSA) nanoparticles (ANPs) loaded with Cur (Cur@ANPs), Dox (Dox@ANPs), or both RESEARCH ARTICLE S. M. Motevalli et al.

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Effect of lysosomotropic molecules on cellular homeostasis

Cited by 63 publications

References 80 publications

Targeting cholesterol transport in circulating melanoma cells to inhibit metastasis

Targeting cholesterol transport in circulating melanoma cells to inhibit metastasis

Transcription factor EB influences invasion and migration in oral squamous cell carcinomas

Co-encapsulation of curcumin and doxorubicin in albumin nanoparticles blocks the adaptive treatment tolerance of cancer cells

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