Browse > Article
http://dx.doi.org/10.7314/APJCP.2012.13.2.625

Reversion of Multidrug Resistance by SKI-II in SGC7901/DDP Cells and Exploration of Underlying Mechanisms  

Zhu, Zu-An (Department of Gastroenterology, Affiliated Hospital of Xuzhou Medical College)
Zhu, Zheng-Qiu (Department of Medical Oncology, Affiliated Hospital of Xuzhou Medical College)
Cai, Hong-Xing (Department of Forensic Medicine, Yancheng Health Professional Technology Institute)
Liu, Ying (Department of Pathology, Xuzhou Medical College)
Publication Information
Asian Pacific Journal of Cancer Prevention / v.13, no.2, 2012 , pp. 625-631 More about this Journal
Abstract
In order to investigate whether SKI-II could reverse drug resistance and its possible mechanisms, we treated SGC7901/DDP cells with SKI-II or SKI-II in combination with DDP. Then cell growth, apoptosis, micromorphological changes, and expression of SphK1, P-gp, NF-${\kappa}B$, Bcl-2 and Bax were assessed by MTT assay, flow cytometry, electron microscopy, immunocytochemistry and Western blot assay respectively. SGC7901/DDP cells were insensitive to cisplatin 2.5mg/L, but when pretreated with SKI-II, their proliferation was inhibited by cisplatin 2.5mg/L significantly, the inhibition rate increasing with time and dose. The apoptosis rate was also significantly elevated. Expression of SphK1 and P-gp was decreased significantly, Pearson correlation analysis showing significant correlation between the two (r=0.595, P<0.01). Expression of NF-${\kappa}B$ and Bcl-2 was decreased significantly,while that of Bax was increased, compared to the control group. There were significant correlations between SphK1 and NF-${\kappa}B$(r=0.723, P<0.01), NF-${\kappa}B$ and Bcl-2(r=0.768, P<0.01). All these data indicated that SKI-II could reverse drug resistance of SGC7901/DDP to cisplatin by down-regulating expression of P-gp and up-regulating apoptosis through down-regulation of SphK1. The increased apoptotic sensitivity of SGC7901/DDP to cisplatin was due to the decreasing proportion of Bcl-2/Bax via down-regulating NF-${\kappa}B$.
Keywords
SGC7901/DDP cells; resistance; SKI-II; apoptosis; SphK1;
Citations & Related Records
연도 인용수 순위
  • Reference
1 Andrieu-Abadie N, Levade T (2002). Sphingomyelin hydrolysis during apoptosis. Biochim Biophys Acta, 1585, 126-34.   DOI
2 Bieberich E (2008). Ceramide signaling in cancer and stem cells. Future Lipidol, 3, 273-300.   DOI
3 Bielawska A, Bielawski J, Szulc ZM, et al (2008). Novel analogs of d-e-MAPP and B13, Part 2: Signature effects on bioactive sphingolipids. Bioorg Med Chem, 16, 1032-45.   DOI
4 Bonhoure E, Pchejetski D, Aouali N, et al (2006). Overcoming MDR-associated chemoresistance in HL-60 acute myeloid leukemia cells by targeting sphingosine kinase-1. Leukemia, 20, 95-102.   DOI
5 Cuvillier O (2007). Sphingosine kinase-1-a potential therapeutic target in cancer. Anticancer Drugs, 18, 105-10.   DOI
6 Cuvillier O (2008). Downregulating sphingosine kinase-1 for cancer therapy. Expert Opin Ther Targets, 12 1009-20.   DOI
7 Esteban V, Lorenzo O, Ruperez M (2004). Angiotensin II via ATI and AT2 receptor and NF-kappa B pathway, regulates the inflammatory response in unilateral ureteral obstruction. Am Sec Nephrol, 15, 1514-29.   DOI
8 Fan, T-J, Han L-H, Cong R-S, et al (2005). Caspase family proteases and apoptosis. Acta Biochim Biophys Sin, 37, 719-27.   DOI
9 French KJ, Schrecengost RS, Lee BD, et al (2003). Discovery and evaluation of inhibi-tors of human sphingosine kinase. Cancer Res, 63, 5962-9.
10 French KJ, Upson JJ, Keller SN, et al (2006). Antitumor activity of sphingosine kinase inhibitors. J Pharmacol Exp Ther, 318, 596-603.   DOI
11 Guillermet-Guibert J, Davenne L, Pchejetski D, et al (2009). Targeting the sphingolipid metabolism to defeat pancreatic cancer cell resistance to the chemotherapeutic gemcitabine drug. Mol Cancer Ther, 8, 809-20.   DOI
12 Herr DR, Chun J (2007). Effects of LPA and S1P on the nervous system and implications for their involvement in disease. Curr Drug Targets, 8, 155-67.   DOI
13 Huang Y, Sadee W (2006). Membrane transporters and channels in and -sensitivity of tumor cells. Cancer Lett, 239, 168-82.   DOI
14 Johnson KR, Johnson KY, Crellin HG, et al (2005). Immunohistochemical distribution of sphingosine kinase 1 in normal and tumor lung tissue. J Histochem Cytochem, 53, 1159-66.   DOI
15 Kawamori T, Osta W, Johnson KR, et al (2006). Sphingosine kinase 1 is up-regulated in colon carcinogenesis. FASEB J, 20, 386-8.   DOI
16 Koberle B, Tomicic MT, Usanova S, et al (2010). Cisplatin resistance: preclinical findings and clinical implications. Biochim Biophys Acta, 1806, 172-82.
17 Lee SY, Yuk DY, Song HS, et al (2008). Growth inhibitory effects of obovatol through induction of apoptotic cell death in prostate and colon cancer by blocking of NF-kappaB. Eur J Pharmacol, 582, 17-25.   DOI
18 Lin CF, Chen CL, Chang WT, et al (2005). Bcl-2 rescues ceramide and etoposide-induced mitochondrial apoptosis through blockage of caspase-2 activation. Biol Chem, 280, 23758-65.   DOI
19 Min J, Stegner AL, Alexander H, et al (2004). Overexpression of sphingosine-1-phosphate lyase or inhibition of sphingosine kinase in Dictyostelium discoideum results in a selective increase in sensitivity to platinum-based chemotherapy drugs. Eukaryot Cell, 3, 795-805.   DOI
20 Misao J, Hayakawa Y, Ohno M, et al (1996). Expression of Bcl- 2 protein, an inhibitor of apoptosis and Bax, an accelerator of apoptosis, in ventricular myocytes of human hearts with myocardial infarction. Circulation, 94, 1506-12.   DOI
21 Pilorget A, Demeule M, Barakat S, et al (2007).Modulation of P-glycoprotein function by sphingosine kinase-1 in brain endothelial cells. J Neurochem, 100, 1203-10.   DOI
22 Modrak DE, Gold DV, Goldenberg DM (2006). Sphingolipid targets in cancer therapy. Mol Cancer Ther, 5, 200-8.   DOI
23 Pchejetski D, Doumerc N, Golzio M, et al (2008). Chemosensitizing effects of sphingosine kinase-1 inhibition in prostate cancer cell and animal models. Mol Cancer Ther, 7, 1836-45.
24 Pchejetski D, Golzio M, Bonhoure E, et al (2005). Sphingosine kinase-1 as a chemotherapy sensor in prostate adenocarcinoma cell and mouse models.Cancer Res, 65, 11667-75.   DOI
25 Reynolds CP, Maurer BJ, Kolesnick RN (2004). Ceramide synthesis and metabolism as a target for cancer therapy. Cancer Lett, 206, 169-80.   DOI   ScienceOn
26 Szulc ZM, Bielawski J, Gracz H, et al (2006). Tailoring structure-function and targeting properties of ceramides by site-specific cationization. Bioorg Med Chem, 14, 7083-104.   DOI
27 Tsujimoto Y (2002). Bcl-2 family of proteins: life-or-death switch in mitochondria. Biosci Rep, 22, 47-58.   DOI   ScienceOn
28 Van Brocklyn JR, Jackson CA, Pearl DK, et al (2005). Sphingosine kinase-1 expression correlates with poor survival ofpatients with glioblastoma multiforme: roles of sphingosine kinase isoforms in growth of glioblastoma cell lines. J Neuropathol Exp Neurol, 64, 695-705.   DOI
29 Veldman RJ, Zerp S, van Blitterswijk WJ, et al (2004). N-hexanoyl-sphingomyelin potentiates in vitro doxorubicin cytotoxicity by enhancing its cellular influx. Br Cancer, 90, 917-25.   DOI
30 Xie Z, Koyama T, Suzuki J, et al (2001). Coronary reperfusion following ischemia: different expression of bcl-2 and bax protein, and cardiomyocyte apoptosis. Jpn Heart, 42, 759-70.   DOI