Restoring sensitivity to oxaliplatin by a novel approach in gemcitabine-resistant pancreatic cancer cells in vitro and in vivo.
Oxaliplatin (OxP) has been used in combination therapy with gemcitabine for the treatment of pancreatic cancer (PC), but the beneficial effect was marginal, which is believed to be due to de novo and acquired drug resistance of PC. Here, we report our in vitro and in vivo preclinical evidence in support of chemosensitization of drug-resistant cells by a nontoxic chemopreventive agent (genistein). Genistein pretreatment together with low concentration of OxP showed significant reduction in cell viability and colony formation concomitant with increased apoptosis (p < 0.01), which was highly synergistic. Drug resistance of PC is allegedly linked with both constitutive and OxP-induced activation of NF-κB, and we found that inactivation of (nuclear factor kappa B) NF-κB by genistein before treatment of cells with OxP was required for cell killing, which was consistent with the downregulation of NF-κB and its downstream antiapoptotic genes (Bcl-2, XIAPs and survivin). Most importantly, our in vivo experiments using orthotopic mouse model showed significant reduction in tumor size (p < 0.01) and reduction of locoregional lymph node metastasis by combination treatment. These results were also consistent with inactivation of NF-κB and the downregulation of NF-κB downstream genes, decreased proliferation marker (Ki-67) and increased apoptosis (TUNEL) in tumor remnants, all of which was consistent with in vitro findings. From these results, we conclude that genistein sensitizes drug-resistant PC to OxP, which is mechanistically linked with inactivation of NF-κB signaling, resulting in greater antitumor effects, and thus our data suggest that this approach could be useful in improving the treatment outcome for patients diagnosed with PC.
Banerjee
Sanjeev
S
Department of Pathology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Wayne State University, Detroit, MI, USA.
Kong
Dejuan
D
Azmi
Asfar S
AS
Wang
Zhiwei
Z
Ahmad
Aamir
A
Sethi
Seema
S
Sarkar
Fazlul H
FH
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D051379:Mice; D008813:Mice, Inbred ICR; D016513:Mice, SCID; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D000077150:Oxaliplatin; D010190:Pancreatic Neoplasms / Q000473:pathology*; D000093542:Gemcitabine
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D003841:Deoxycytidine; D000093542:Gemcitabine
Pancreas. 2004 May;28(4):e90-5
15097869
Expert Opin Pharmacother. 2007 Nov;8(16):2719-27
17956194
Cancer Res. 2005 Oct 1;65(19):9064-72
16204081
CA Cancer J Clin. 2009 Jul-Aug;59(4):225-49
19474385
Cancer Res. 2009 Jul 1;69(13):5575-83
19549912
Clin Cancer Res. 2008 Dec 15;14(24):8143-51
19088029
Anticancer Drugs. 2009 Sep;20(8):713-22
19617819
Eur J Nutr. 2001 Aug;40(4):135-46
11905954
Clin Cancer Res. 2009 Oct 15;15(20):6367-77
19808866
Int J Cancer. 2007 Feb 15;120(4):906-17
17131310
J Clin Oncol. 2009 Jun 1;27(16):2712-25
19414669
Cancer. 2009 May 15;115(10):2165-76
19288574
J Chemother. 2005 Feb;17(1):86-95
15828450
Nutr Cancer. 2009;61(5):587-97
19838932
Dig Dis Sci. 2009 Jan;54(1):89-96
18594980
Cancer Res. 2009 Jul 1;69(13):5592-600
19531648
Cancer Metastasis Rev. 2002;21(3-4):265-80
12549765
Int J Cancer. 2003 Jul 20;105(6):735-46
12767057
Cancer Lett. 2009 Jun 18;278(2):201-209
19231069
Cancer Treat Rev. 2009 Nov;35(7):597-607
19660870
Semin Oncol. 2007 Aug;34(4):347-53
17674963
Drugs. 2006;66(8):1059-72
16789792
Kidney Int. 2008 Dec;74(12):1538-47
18716605
Biochem Biophys Res Commun. 2005 Jul 1;332(2):433-40
15896711
Cancer Lett. 2008 Oct 8;269(2):226-42
18492603
Recent Results Cancer Res. 2008;177:151-64
18084957
Cancer Invest. 2003;21(5):744-57
14628433
Mol Cancer Res. 2010 Jan;8(1):24-34
20068070
Biochem Pharmacol. 2004 Jun 1;67(11):2031-8
15135300
Invest New Drugs. 2010 Dec;28(6):812-24
19777160
In Vivo. 2005 Jan-Feb;19(1):61-7
15796156
Semin Oncol. 2007 Apr;34(2 Suppl 1):S25-30
17449349
Cancer Res. 2006 Nov 1;66(21):10553-9
17079479
Cancer Lett. 2010 Jun 1;292(1):54-63
19959278
Cancer Invest. 2005;23(1):9-12
15779862
Cancer Treat Rev. 2009 Dec;35(8):676-84
19758760
Cancer Sci. 2003 May;94(5):467-72
12824895
Oncogene. 2003 May 22;22(21):3243-51
12761494
Cancer Res. 2004 Jun 15;64(12):4346-52
15205350
Cancer Lett. 2010 May 1;291(1):90-8
19880242