Galactosylated Poly(Ethyleneglycol)‐Lithocholic Acid Selectively Kills Hepatoma Cells, While Sparing Normal Liver Cells

Gankhuyag, Nomundelger; Singh, Bijay; Maharjan, Sushila; Choi, Yun‐Jaie; Cho, Chong‐Su; Cho, Myung‐Haing

doi:10.1002/mabi.201400475

Cited by 13 publications

(7 citation statements)

References 27 publications

(29 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…2). The selectiveness of LCA in killing cancer cells has recently been demonstrated in hepatocytes, where galactosylated poly(ethylene glycol)-conjugated LCA was toxic to HepG2 human hepatocarcinoma cells, but not to immortalized human LO2 liver cells (Gankhuyag et al, 2015). Furthermore, we have previously shown that LCA killed neuroblastoma cells, whilst sparing normal neuronal cells (Goldberg et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Lithocholic acid induces endoplasmic reticulum stress, autophagy and mitochondrial dysfunction in human prostate cancer cells

Gafar

Draz

Goldberg

et al. 2016

PeerJ

View full text Add to dashboard Cite

Lithocholic acid (LCA) is a secondary bile acid that is selectively toxic to human neuroblastoma, breast and prostate cancer cells, whilst sparing normal cells. We previously reported that LCA inhibited cell viability and proliferation and induced apoptosis and necrosis of androgen-dependent LNCaP and androgen-independent PC-3 human prostate cancer cells. In the present study, we investigated the roles of endoplasmic reticulum (ER) stress, autophagy and mitochondrial dysfunction in the toxicity of LCA in PC-3 and autophagy deficient, androgen-independent DU-145 cells. LCA induced ER stress-related proteins, such as CCAAT-enhancer-binding protein homologous protein (CHOP), and the phosphorylation of eukaryotic initiation factor 2-alpha (p-eIF2α) and c-Jun N-terminal kinases (p-JNK) in both cancer cell-types. The p53 upregulated modulator of apoptosis (PUMA) and B cell lymphoma-like protein 11 (BIM) levels were decreased at overtly toxic LCA concentrations, although PUMA levels increased at lower LCA concentrations in both cell lines. LCA induced autophagy-related conversion of microtubule-associated proteins 1A/1B light chain 3B (LC3BI–LC3BII), and autophagy-related protein ATG5 in PC-3 cells, but not in autophagy-deficient DU-145 cells. LCA (>10 µM) increased levels of reactive oxygen species (ROS) concentration-dependently in PC-3 cells, whereas ROS levels were not affected in DU-145 cells. Salubrinal, an inhibitor of eIF2α dephosphorylation and ER stress, reduced LCA-induced CHOP levels slightly in PC-3, but not DU-145 cells. Salubrinal pre-treatment increased the cytotoxicity of LCA in PC-3 and DU-145 cells and resulted in a statistically significant loss of cell viability at normally non-toxic concentrations of LCA. The late-stage autophagy inhibitor bafilomycin A1 exacerbated LCA toxicity at subtoxic LCA concentrations in PC-3 cells. The antioxidant α-tocotrienol strongly inhibited the toxicity of LCA in PC-3 cells, but not in DU-145 cells. Collectively, although LCA induces autophagy and ER stress in PC-3 cells, these processes appear to be initially of protective nature and subsequently consequential to, but not critical for the ROS-mediated mitochondrial dysfunction and cytotoxicity of LCA. The full mechanism of LCA-induced mitochondrial dysfunction and cytotoxicity in the similarly sensitive DU-145 cells remains to be elucidated.

show abstract

Section: Discussionmentioning

confidence: 99%

Lithocholic acid induces endoplasmic reticulum stress, autophagy and mitochondrial dysfunction in human prostate cancer cells

Gafar

Draz

Goldberg

et al. 2016

PeerJ

View full text Add to dashboard Cite

show abstract

“…LCA triggered concentration-dependent death of PC3 and DU-145 cells via apoptotic and necrotic pathways (Fig 2). The selectiveness of LCA in killing cancer cells has recently been demonstrated in hepatocytes, where galactosylated poly(ethylene glycol)-conjugated LCA was toxic to HepG2 human hepatocarcinoma cells, but not to immortalized human LO2 liver cells (Gankhuyag et al, 2015). Furthermore, we have previously shown that LCA killed neuroblastoma cells, whilst sparing normal neuronal cells (Goldberg et al, 2011).…”

Section: Lca Induces Selective Cancer Cell Deathmentioning

confidence: 73%

Peer Review #1 of "Lithocholic acid induces endoplasmic reticulum stress, autophagy and mitochondrial dysfunction in human prostate cancer cells (v0.1)"

Huan¹

2016

View full text Add to dashboard Cite

Lithocholic acid (LCA) is a secondary bile acid that is selectively toxic to human neuroblastoma, breast and prostate cancer cells, whilst sparing normal cells. We previously reported that LCA inhibited cell viability and proliferation and induced apoptosis and necrosis of androgen-dependent LNCaP and androgen-independent PC-3 human prostate cancer cells. In the present study, we investigated the roles of endoplasmic reticulum (ER) stress, autophagy and mitochondrial dysfunction in the toxicity of LCA in PC-3 and autophagy deficient, androgen-independent DU-145 cells. LCA induced ER stressrelated proteins, such as CCAAT-enhancer-binding protein homologous protein (CHOP), and the phosphorylation of eukaryotic initiation factor 2-alpha (p-eIF2α) and c-Jun N-terminal kinases (p-JNK) in both cancer cell-types. The p53 upregulated modulator of apoptosis (PUMA) and B cell lymphoma-like protein 11 (BIM) levels were decreased at overtly toxic LCA concentrations, although PUMA levels increased at lower LCA concentrations in both cell lines. LCA induced autophagy-related conversion of microtubule-associated proteins 1A/1B light chain 3B (LC3BI to LC3BII), and autophagy-related protein ATG5 in PC-3 cells, but not in autophagy-deficient DU-145 cells. LCA (>10 μM) increased levels of reactive oxygen species (ROS) concentration-dependently in PC-3 cells, whereas ROS levels were not affected in DU-145 cells. Salubrinal, an inhibitor of eIF2α dephosphorylation and ER stress, reduced LCA-induced CHOP levels slightly in PC-3, but not DU-145 cells. Salubrinal pre-treatment increased the cytotoxicity of LCA in PC-3 and DU-145 cells and resulted in a statistically significant loss of cell viability at normally non-toxic concentrations of LCA. The late-stage autophagy inhibitor bafilomycin A1 exacerbated LCA toxicity at subtoxic LCA concentrations in PC-3 cells. The antioxidant α-tocotrienol strongly inhibited the toxicity of

show abstract

“…Conversely, for the UiO‐66‐TPP group (Figure c), an obvious overlap of the green color from mitochondria and the red color from NMOFs could be observed, resulting in an orange‐yellow color in merged image. Especially, the more significant colocalization could be obtained when the dual‐targeting UiO‐66‐TPP‐FA (Figure d) was internalized, strongly proving that these NMOFs could quickly escape from the lysosomes and thus accumulate into the mitochondria with the aid of the electrostatic interaction between positively charged TPP molecules and mitochondrial membranes with negative charges …”

Section: Resultsmentioning

confidence: 93%

Mitochondria‐Targeted Nanoscale MOFs for Improved Photodynamic Therapy

et al. 2019

View full text Add to dashboard Cite

Due to the existence of hypoxic microenvironment, the efficacy of photodynamic therapy (PDT) is frequently weakened. As a result, targeted treatment toward oxygenrich mitochondria is considered as a promising cancer therapy. Herein, both triphenylphosphine (TPP) and folic acid (FA) are simultaneously grafted onto nanoscale metal-organic frameworks (NMOFs) to realize dual-targeting delivery of the nanoplatforms into cancer cells and their mitochondria via the proposed phosphorylation modification strategy. A large amount of highly efficient photosensitizer of porphyrinic molecules is integrated into the NMOFs with a uniform particle size of about 65 nm. Thanks to the strong ZrÀ OÀ P bonding, a dense coverage of phosphonate-conjugating targeting molecules on NMOFs is obtained and each surficial unsaturated ZrÀ O cluster is adequately occupied. The resultant dual-targeting NMOFs feature high biostability and biocompatibility, as well as improved cellular uptake and mitochondrial accumulation. The PDT efficacy of these dualtargeting NMOFs is significantly improved with a low IC 50 of 0.74 μM upon 10 min light radiation, which is at least four times higher than that of non-targeting counterparts. This phosphorylation strategy would be hopeful for immobilizing a variety of biogenic groups on NMOFs to make them targetable to various specific organelles and to improve the therapy efficacy on related diseases.

show abstract

Galactosylated Poly(Ethyleneglycol)‐Lithocholic Acid Selectively Kills Hepatoma Cells, While Sparing Normal Liver Cells

Cited by 13 publications

References 27 publications

Lithocholic acid induces endoplasmic reticulum stress, autophagy and mitochondrial dysfunction in human prostate cancer cells

Lithocholic acid induces endoplasmic reticulum stress, autophagy and mitochondrial dysfunction in human prostate cancer cells

Peer Review #1 of "Lithocholic acid induces endoplasmic reticulum stress, autophagy and mitochondrial dysfunction in human prostate cancer cells (v0.1)"

Mitochondria‐Targeted Nanoscale MOFs for Improved Photodynamic Therapy

Contact Info

Product

Resources

About