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Cisplatin in 5% Ethanol Eradicates Cisplatin-Resistant Lung Tumor by Killing Lung Cancer Side Population (SP) Cells and Non-SP Cells.

Niu Q, Wang W, Li Y, Ruden DM, Li Q, Wang F - Front Genet (2013)

Bottom Line: Furthermore, cytotoxic cisplatin (DDP) in 5% (vol/vol) ethanol kills SP plus non-SP cancer cells better than either treatment alone in eradicating chemoresistant lung tumors.We found that 5% ethanol did not reduce ABCG2 protein levels, but significantly reduced ABCG2 protein function by a Hoechst 33342 extrusion assay, an ATPase activity assay, and transmission electron microscopy.In DDP-resistant A549/DDP lung tumor-bearing Balb/C nude mice, intratumoral injection of 5% ethanol-DDP regressed tumors and significantly improved survivals compared with 5% ethanol, DDP alone, or control.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Oncology, No. 309 People's Liberation Army Hospital Beijing, People's Republic of China.

ABSTRACT
Cancer side population (SP) cells with cancer stem cell-like properties are thought to be responsible for lung cancer chemotherapy resistance and currently no drug can efficiently target them. Breast cancer resistance protein (BRCP/ABCG2) is a major drug transporter in protecting lung cancer SP cells from cytotoxic agents. We showed that a low concentration of ethanol, which inhibits many membrane proteins, inhibits ABCG2 in lung cancer SP cells. Furthermore, cytotoxic cisplatin (DDP) in 5% (vol/vol) ethanol kills SP plus non-SP cancer cells better than either treatment alone in eradicating chemoresistant lung tumors. We found that 5% ethanol did not reduce ABCG2 protein levels, but significantly reduced ABCG2 protein function by a Hoechst 33342 extrusion assay, an ATPase activity assay, and transmission electron microscopy. Further, DDP in 5% ethanol (5% ethanol-DDP) induced apoptosis of the SP plus non-SP cancer cells both in vitro and in vivo. In DDP-resistant A549/DDP lung tumor-bearing Balb/C nude mice, intratumoral injection of 5% ethanol-DDP regressed tumors and significantly improved survivals compared with 5% ethanol, DDP alone, or control. Intratumoral injection of 5% ethanol-DDP helped eradicate tumors in 30% (3/10) of the mice after 4 weeks treatment. By killing SP and non-SP cancer cells, 5% ethanol-DDP could eradicate DDP-resistant lung tumor and extend survival, providing a novel way to improve chemoresistant lung cancer survival for clinic.

No MeSH data available.


Related in: MedlinePlus

(A) Apoptosis analysis of SP cells treated with 5% ethanol, DDP, 5% ethanol–DDP, and control by FACS. (a) Apoptosis of control SP cells. (b) Apoptosis of 5% ethanol-treated SP cells. (c) Apoptosis of DDP-treated SP cells. (d) Apoptosis of 5% ethanol–DDP-treated SP cells. (B) Apoptosis rate of treated SP cells. The most significant apoptosis rate was found in 5% ethanol–DDP-treated SP cells.
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Figure 2: (A) Apoptosis analysis of SP cells treated with 5% ethanol, DDP, 5% ethanol–DDP, and control by FACS. (a) Apoptosis of control SP cells. (b) Apoptosis of 5% ethanol-treated SP cells. (c) Apoptosis of DDP-treated SP cells. (d) Apoptosis of 5% ethanol–DDP-treated SP cells. (B) Apoptosis rate of treated SP cells. The most significant apoptosis rate was found in 5% ethanol–DDP-treated SP cells.

Mentions: The SP cells apoptosis rates in different treatment groups were: 0.76% ± 0.1% for control, 3.03% ± 0.5% for DDP, 1.86% ± 0.2% for 5% ethanol, and 93.32% ± 7.63% for 5% ethanol–DDP (Figure 2A). Compared with control, 5% ethanol–DDP induced SP cells apoptosis significantly (93.32% ± 7.63% vs. 0.76% ± 0.1%, p < 0.05; Figure 2B). In non-SP cells, both 5% ethanol–DDP and DDP induced apoptosis significantly (98.32% ± 0.8% for 5% ethanol–DDP vs. 4.5% ± 0.5% for control, p < 0.05; 60.16% ± 6.8% for DDP vs. 4.5% ± 0.5% for control, p < 0.05), but 5% ethanol did not (6.4% ± 0.5% for 5% ethanol vs. 4.5% ± 0.5% for control, p > 0.05) compared with control.


Cisplatin in 5% Ethanol Eradicates Cisplatin-Resistant Lung Tumor by Killing Lung Cancer Side Population (SP) Cells and Non-SP Cells.

Niu Q, Wang W, Li Y, Ruden DM, Li Q, Wang F - Front Genet (2013)

(A) Apoptosis analysis of SP cells treated with 5% ethanol, DDP, 5% ethanol–DDP, and control by FACS. (a) Apoptosis of control SP cells. (b) Apoptosis of 5% ethanol-treated SP cells. (c) Apoptosis of DDP-treated SP cells. (d) Apoptosis of 5% ethanol–DDP-treated SP cells. (B) Apoptosis rate of treated SP cells. The most significant apoptosis rate was found in 5% ethanol–DDP-treated SP cells.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3756282&req=5

Figure 2: (A) Apoptosis analysis of SP cells treated with 5% ethanol, DDP, 5% ethanol–DDP, and control by FACS. (a) Apoptosis of control SP cells. (b) Apoptosis of 5% ethanol-treated SP cells. (c) Apoptosis of DDP-treated SP cells. (d) Apoptosis of 5% ethanol–DDP-treated SP cells. (B) Apoptosis rate of treated SP cells. The most significant apoptosis rate was found in 5% ethanol–DDP-treated SP cells.
Mentions: The SP cells apoptosis rates in different treatment groups were: 0.76% ± 0.1% for control, 3.03% ± 0.5% for DDP, 1.86% ± 0.2% for 5% ethanol, and 93.32% ± 7.63% for 5% ethanol–DDP (Figure 2A). Compared with control, 5% ethanol–DDP induced SP cells apoptosis significantly (93.32% ± 7.63% vs. 0.76% ± 0.1%, p < 0.05; Figure 2B). In non-SP cells, both 5% ethanol–DDP and DDP induced apoptosis significantly (98.32% ± 0.8% for 5% ethanol–DDP vs. 4.5% ± 0.5% for control, p < 0.05; 60.16% ± 6.8% for DDP vs. 4.5% ± 0.5% for control, p < 0.05), but 5% ethanol did not (6.4% ± 0.5% for 5% ethanol vs. 4.5% ± 0.5% for control, p > 0.05) compared with control.

Bottom Line: Furthermore, cytotoxic cisplatin (DDP) in 5% (vol/vol) ethanol kills SP plus non-SP cancer cells better than either treatment alone in eradicating chemoresistant lung tumors.We found that 5% ethanol did not reduce ABCG2 protein levels, but significantly reduced ABCG2 protein function by a Hoechst 33342 extrusion assay, an ATPase activity assay, and transmission electron microscopy.In DDP-resistant A549/DDP lung tumor-bearing Balb/C nude mice, intratumoral injection of 5% ethanol-DDP regressed tumors and significantly improved survivals compared with 5% ethanol, DDP alone, or control.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Oncology, No. 309 People's Liberation Army Hospital Beijing, People's Republic of China.

ABSTRACT
Cancer side population (SP) cells with cancer stem cell-like properties are thought to be responsible for lung cancer chemotherapy resistance and currently no drug can efficiently target them. Breast cancer resistance protein (BRCP/ABCG2) is a major drug transporter in protecting lung cancer SP cells from cytotoxic agents. We showed that a low concentration of ethanol, which inhibits many membrane proteins, inhibits ABCG2 in lung cancer SP cells. Furthermore, cytotoxic cisplatin (DDP) in 5% (vol/vol) ethanol kills SP plus non-SP cancer cells better than either treatment alone in eradicating chemoresistant lung tumors. We found that 5% ethanol did not reduce ABCG2 protein levels, but significantly reduced ABCG2 protein function by a Hoechst 33342 extrusion assay, an ATPase activity assay, and transmission electron microscopy. Further, DDP in 5% ethanol (5% ethanol-DDP) induced apoptosis of the SP plus non-SP cancer cells both in vitro and in vivo. In DDP-resistant A549/DDP lung tumor-bearing Balb/C nude mice, intratumoral injection of 5% ethanol-DDP regressed tumors and significantly improved survivals compared with 5% ethanol, DDP alone, or control. Intratumoral injection of 5% ethanol-DDP helped eradicate tumors in 30% (3/10) of the mice after 4 weeks treatment. By killing SP and non-SP cancer cells, 5% ethanol-DDP could eradicate DDP-resistant lung tumor and extend survival, providing a novel way to improve chemoresistant lung cancer survival for clinic.

No MeSH data available.


Related in: MedlinePlus