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Giant Lysosomes as a Chemotherapy Resistance Mechanism in Hepatocellular Carcinoma Cells.

Colombo F, Trombetta E, Cetrangolo P, Maggioni M, Razini P, De Santis F, Torrente Y, Prati D, Torresani E, Porretti L - PLoS ONE (2014)

Bottom Line: ABC expression analyses showed that the main ABC protein harboured by all of the cell lines was PGP, whose expression was not limited to the cell membrane but was also found on lysosomes.The findings of this study demonstrate the involvement of PGP-positive lysosomes in drug sequestration and MDR in HCC cell lines.The possibility of modulating this mechanism using PGP inhibitors could lead to the development of new targeted strategies to enhance HCC treatment.

View Article: PubMed Central - PubMed

Affiliation: Clinical Chemistry and Microbiology Laboratory, Flow Cytometry and Experimental Hepatology Service, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

ABSTRACT
Despite continuous improvements in therapeutic protocols, cancer-related mortality is still one of the main problems facing public health. The main cause of treatment failure is multi-drug resistance (MDR: simultaneous insensitivity to different anti-cancer agents), the underlying molecular and biological mechanisms of which include the activity of ATP binding cassette (ABC) proteins and drug compartmentalisation in cell organelles. We investigated the expression of the main ABC proteins and the role of cytoplasmic vacuoles in the MDR of six hepatocellular carcinoma (HCC) cell lines, and confirmed the accumulation of the yellow anti-cancer drug sunitinib in giant (four lines) and small cytoplasmic vacuoles of lysosomal origin (two lines). ABC expression analyses showed that the main ABC protein harboured by all of the cell lines was PGP, whose expression was not limited to the cell membrane but was also found on lysosomes. MTT assays showed that the cell lines with giant lysosomes were more resistant to sorafenib treatment than those with small lysosomes (p<0.01), and that verapamil incubation can revert this resistance, especially if it is administered after drug pre-incubation. The findings of this study demonstrate the involvement of PGP-positive lysosomes in drug sequestration and MDR in HCC cell lines. The possibility of modulating this mechanism using PGP inhibitors could lead to the development of new targeted strategies to enhance HCC treatment.

No MeSH data available.


Related in: MedlinePlus

Sunitinib accumulation in cytoplasmic vesicles of HCC cell lines.Representative pictures of cell lines cultured without (left) or with (right) sunitinib 12 µM. Cytoplasmic vesicles are visible in the Hep3B and SNU475 cells only after sunitinib incubation. Original magnification 20x.
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pone-0114787-g001: Sunitinib accumulation in cytoplasmic vesicles of HCC cell lines.Representative pictures of cell lines cultured without (left) or with (right) sunitinib 12 µM. Cytoplasmic vesicles are visible in the Hep3B and SNU475 cells only after sunitinib incubation. Original magnification 20x.

Mentions: Under basal conditions, the HCC cell lines showed different patterns of vesicle expression: the HepG2 and Hcc-1 lines had 1–2 large cytoplasmic vacuoles per cell; the HuH7 and PLC/PRF/5 lines had 1–2 medium-sized vesicles; and the Hep3B and SNU475 had no visible vesicles. After sunitinib incubation, large yellow vesicles were visible in the HepG2, Hcc-1, HuH7 and PLC/PRF/5 cells, whereas the Hep3B and SNU475 cells showed only very small yellow cell vesicles (Fig. 1).


Giant Lysosomes as a Chemotherapy Resistance Mechanism in Hepatocellular Carcinoma Cells.

Colombo F, Trombetta E, Cetrangolo P, Maggioni M, Razini P, De Santis F, Torrente Y, Prati D, Torresani E, Porretti L - PLoS ONE (2014)

Sunitinib accumulation in cytoplasmic vesicles of HCC cell lines.Representative pictures of cell lines cultured without (left) or with (right) sunitinib 12 µM. Cytoplasmic vesicles are visible in the Hep3B and SNU475 cells only after sunitinib incubation. Original magnification 20x.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4262459&req=5

pone-0114787-g001: Sunitinib accumulation in cytoplasmic vesicles of HCC cell lines.Representative pictures of cell lines cultured without (left) or with (right) sunitinib 12 µM. Cytoplasmic vesicles are visible in the Hep3B and SNU475 cells only after sunitinib incubation. Original magnification 20x.
Mentions: Under basal conditions, the HCC cell lines showed different patterns of vesicle expression: the HepG2 and Hcc-1 lines had 1–2 large cytoplasmic vacuoles per cell; the HuH7 and PLC/PRF/5 lines had 1–2 medium-sized vesicles; and the Hep3B and SNU475 had no visible vesicles. After sunitinib incubation, large yellow vesicles were visible in the HepG2, Hcc-1, HuH7 and PLC/PRF/5 cells, whereas the Hep3B and SNU475 cells showed only very small yellow cell vesicles (Fig. 1).

Bottom Line: ABC expression analyses showed that the main ABC protein harboured by all of the cell lines was PGP, whose expression was not limited to the cell membrane but was also found on lysosomes.The findings of this study demonstrate the involvement of PGP-positive lysosomes in drug sequestration and MDR in HCC cell lines.The possibility of modulating this mechanism using PGP inhibitors could lead to the development of new targeted strategies to enhance HCC treatment.

View Article: PubMed Central - PubMed

Affiliation: Clinical Chemistry and Microbiology Laboratory, Flow Cytometry and Experimental Hepatology Service, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

ABSTRACT
Despite continuous improvements in therapeutic protocols, cancer-related mortality is still one of the main problems facing public health. The main cause of treatment failure is multi-drug resistance (MDR: simultaneous insensitivity to different anti-cancer agents), the underlying molecular and biological mechanisms of which include the activity of ATP binding cassette (ABC) proteins and drug compartmentalisation in cell organelles. We investigated the expression of the main ABC proteins and the role of cytoplasmic vacuoles in the MDR of six hepatocellular carcinoma (HCC) cell lines, and confirmed the accumulation of the yellow anti-cancer drug sunitinib in giant (four lines) and small cytoplasmic vacuoles of lysosomal origin (two lines). ABC expression analyses showed that the main ABC protein harboured by all of the cell lines was PGP, whose expression was not limited to the cell membrane but was also found on lysosomes. MTT assays showed that the cell lines with giant lysosomes were more resistant to sorafenib treatment than those with small lysosomes (p<0.01), and that verapamil incubation can revert this resistance, especially if it is administered after drug pre-incubation. The findings of this study demonstrate the involvement of PGP-positive lysosomes in drug sequestration and MDR in HCC cell lines. The possibility of modulating this mechanism using PGP inhibitors could lead to the development of new targeted strategies to enhance HCC treatment.

No MeSH data available.


Related in: MedlinePlus