Intricatinol synergistically enhances the anticancerous activity of cisplatin in human A549 cells via p38 MAPK/p53 signalling

被引:23
作者
Singh, Vipendra Kumar [1 ,2 ]
Arora, Deepika [1 ]
Satija, Neeraj Kumar [3 ]
Khare, Puneet [3 ]
Roy, Somendu Kumar [4 ]
Sharma, Pradeep Kumar [1 ,2 ]
机构
[1] CSIR, IITR, Food Drug & Chem Toxicol Grp, Environm Carcinogenesis Lab, Vishvigyan Bhawan,31,Mahatma Gandhi Marg, Lucknow 226001, Uttar Pradesh, India
[2] Acad Sci & Innovat Res AcSIR, CSIR IITR Campus, Lucknow, Uttar Pradesh, India
[3] CSIR, IITR, Syst Toxicol & Hlth Risk Assessment Grp, Dev Toxicol Lab, Vishvigyan Bhawan,31,Mahatma Gandhi Marg, Lucknow 226001, Uttar Pradesh, India
[4] CSIR, IITR, Regulatory Toxicol Grp, Analyt Chem Lab, Vishvigyan Bhawan,31,Mahatma Gandhi Marg, Lucknow 226001, Uttar Pradesh, India
关键词
Intricatinol; Lung adenocarcinoma; Cisplatin; Apoptosis; Phytochemicals; LUNG-CANCER; IN-VITRO; PHYTOCHEMICALS; INHIBITION; CURCUMIN; CHEMOPREVENTION; ACTIVATION; APOPTOSIS; THERAPY; GROWTH;
D O I
10.1007/s10495-017-1404-0
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Platinum containing drugs are widely used to treat advanced lung carcinomas. However, their clinical success is still limited due to severe side effects, and drug resistance. Alternative approaches are warranted to augment efficacy of platinum based chemotherapeutic drugs with minimal side effects. Intricatinol (INT), a homoisoflavonoid, has been shown to possess anti-tubercular, antioxidant, hypoglycaemic, and hypolipidemic activity. However, its anticancer activity largely remains unknown. In the present study, we have evaluated anticancer potential of INT alone or in combination with cisplatin (CIS) in non-small cell lung carcinoma (A549) cells. Treatment with INT alone reduced the viability of A549 cells in a dose-dependent manner. Interestingly, the combination of low doses of INT and CIS exerted a synergistic effect and induced apoptosis as evident by DNA fragmentation and Annexin V positive cells. Enhanced Bax:Bcl-2 ratio, loss of Delta psi m, cytochrome c release, cleavage of caspase 3 and PARP1 strongly corroborated our findings. Further, increased expression of p53, p38 MAPK and their phosphorylated counterparts, loss of clonogenicity and reduced migration potential were also recorded with INT + CIS treatment. Most interestingly, INT could not induce any significant cell death in primary mouse embryonic fibroblasts (MEFs). Moreover, no additive or synergistic effect was noted with INT + CIS in MEFs under similar treatment conditions. In conclusion, INT has a selective anticancer potential and could synergize cytotoxicity of CIS. Therefore, the combination of INT and CIS may serve as an effective anticancer strategy for the treatment of non-small cell lung carcinoma.
引用
收藏
页码:1273 / 1286
页数:14
相关论文
共 42 条
[1]  
Akcali Z, 2008, TUMORI J, V94, P474
[2]  
[Anonymous], PHARMACOLOGYONLINE
[3]  
[Anonymous], 2014, COLD SPRING HARB PRO
[4]   Deltamethrin induced RIPK3-mediated caspase-independent non-apoptotic cell death in rat primary hepatocytes [J].
Arora, Deepika ;
Siddiqui, Mohammed Haris ;
Sharma, Pradeep Kumar ;
Shukla, Yogeshwer .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 2016, 479 (02) :217-223
[5]   Treatment options for relapsed small-cell lung cancer [J].
Azim, Hatem A., Jr. ;
Ganti, Apar Kishor .
ANTI-CANCER DRUGS, 2007, 18 (03) :255-261
[6]   A combination of 2-deoxy-D-glucose and 6-aminonicotinamide induces cell cycle arrest and apoptosis selectively in irradiated human malignant cells [J].
Bhardwaj, Richa ;
Sharma, Pradeep K. ;
Jadon, S. P. S. ;
Varshney, Rajeev .
TUMOR BIOLOGY, 2012, 33 (04) :1021-1030
[7]   Phase II Trial of Irinotecan and Carboplatin for Extensive or Relapsed Small-Cell Lung Cancer [J].
Chen, Gigi ;
Huynh, Minh ;
Fehrenbacher, Lou ;
West, Howard ;
Lara, Primo N., Jr. ;
Yavorkovsky, Leonid L. ;
Russin, Michael ;
Goldstein, Desiree ;
Gandara, David ;
Lau, Derick .
JOURNAL OF CLINICAL ONCOLOGY, 2009, 27 (09) :1401-1404
[8]  
Chen SS, 2012, PLOS ONE, V7, DOI [10.1371/journal.pone.0036784, 10.1371/journal.pone.0050456, 10.1371/journal.pone.0049275, 10.1371/journal.pone.0045763]
[9]   Drug Combination Studies and Their Synergy Quantification Using the Chou-Talalay Method [J].
Chou, Ting-Chao .
CANCER RESEARCH, 2010, 70 (02) :440-446
[10]   MKP1 mediates chemosensitizer effects of E1a in response to cisplatin in non-small cell lung carcinoma cells [J].
Cimas, Francisco J. ;
Callejas-Valera, Juan L. ;
Pascual-Serra, Raquel ;
Garcia-Cano, Jesus ;
Garcia-Gil, Elena ;
De la Cruz-Morcillo, Miguel ;
Ortega-Muelas, Marta ;
Serrano-Oviedo, Leticia ;
Gutkind, J. Silvio ;
Sanchez-Prieto, Ricardo .
ONCOTARGET, 2015, 6 (42) :44095-44107