Antineoplastic Effect of a Combined Mitotane Treatment/Ionizing Radiation in Adrenocortical Carcinoma: A Preclinical Study

被引:12
作者
Cerquetti, Lidia [1 ]
Bucci, Barbara [2 ]
Carpinelli, Giulia [3 ]
Lardo, Pina [1 ]
Proietti, Antonella [4 ]
Saporito, Raffaele [2 ]
Rindi, Guido [5 ]
Petrangeli, Elisa [6 ,7 ]
Toscano, Vincenzo [1 ]
Stigliano, Antonio [1 ]
机构
[1] Sapienza Univ Rome, St Andrea Hosp, Dept Clin & Mol Med, Endocrinol, I-00189 Rome, Italy
[2] UOC Pathol Clin San Pietro Hosp Fatebenefratelli, I-00189 Rome, Italy
[3] Ist Super Sanita, Dept Cellular Biol & Neurosci, I-00161 Rome, Italy
[4] Sapienza Univ Rome, St Andrea Hosp, Dept Clin & Mol Med, Diagnost Lab Unit, I-00189 Rome, Italy
[5] Univ Catholic, Pathol Unit, I-00168 Rome, Italy
[6] CNR, Inst Mol Biol & Pathol, I-00185 Rome, Italy
[7] Sapienza Univ Rome, Dept Mol Med, I-00161 Rome, Italy
关键词
adrenal cancer; mitotane; radiotherapy; adjuvant therapy; small animal magnetic resonance imaging; mismatch repair enzymes; CLINICAL-PRACTICE GUIDELINES; ADJUVANT MITOTANE; TARGETED THERAPY; DOWN-REGULATION; ADRENAL CANCER; RADIOTHERAPY; MANAGEMENT; CELLS; EXPRESSION; DEFECTS;
D O I
10.3390/cancers11111768
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Mitotane (MTT) is an adrenolytic drug used in adjuvant and advanced treatments of adrenocortical carcinoma (ACC). Ionizing radiation (IR) is also used in adrenal cancer treatment, even though its biological action remains unknown. To provide a reliable in vivo preclinical model of ACC, we used mouse xenografts bearing human ACC to test the effects of MTT and IR alone and in combination. We evaluated tumor growth inhibition by the RECIST criteria and analyzed the cell cycle by flow cytometry (FCM). In the xenograft ACC model treated with MTT/IR in combination, we observed a marked inhibition of tumor growth, with strong tumor regression (p < 0.0001) compared to MTT and IR given alone (p < 0.05). The MTT results confirm its antisteroidogenic activity (p < 0.05) in the xenograft ACC model, revealing its ability to render cancer cells more prone to radiotherapy treatment. In addition, to explain the biological effect of these treatments on the Mismatch Repair System (MMR), we interfered with the MSH2 gene expression in untreated and MTT/IR-treated H295R and SW13 cell lines. Moreover, we observed that upon treatment with MTT/IR to induce DNA damage, MSH2 gene inhibition in both the H295R and SW13 cell lines did not allow DNA damage repair, thus inducing cell death. In conclusion, MTT seems to have a radiosensitizing property and, when given in combination with IR, is able to promote neoplastic growth inhibition, leading to a significant reduction in tumor size due to cell death.
引用
收藏
页数:13
相关论文
共 29 条
[21]   Radiotherapy in Adrenocortical Carcinoma [J].
Polat, Buelent ;
Fassnacht, Martin ;
Pfreundner, Leo ;
Guckenberger, Matthias ;
Bratengeier, Klaus ;
Johanssen, Sarah ;
Kenn, Werner ;
Hahner, Stefanie ;
Allolio, Bruno ;
Flentje, Michael .
CANCER, 2009, 115 (13) :2816-2823
[22]   Adjuvant Radiation Therapy Improves Local Control After Surgical Resection in Patients With Localized Adrenocortical Carcinoma [J].
Sabolch, Aaron ;
Else, Tobias ;
Griffith, Kent A. ;
Ben-Josef, Edgar ;
Williams, Andrew ;
Miller, Barbra S. ;
Worden, Francis ;
Hammer, Gary D. ;
Jolly, Shruti .
INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS, 2015, 92 (02) :252-259
[23]   ADJUVANT AND DEFINITIVE RADIOTHERAPY FOR ADRENOCORTICAL CARCINOMA [J].
Sabolch, Aaron ;
Feng, Mary ;
Griffith, Kent ;
Hammer, Gary ;
Doherty, Gerard ;
Ben-Josef, Edgar .
INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS, 2011, 80 (05) :1477-1484
[24]   Management of patients with adrenal cancer: recommendations of an international consensus conference [J].
Schteingart, DE ;
Doherty, GM ;
Gauger, PG ;
Giordano, TJ ;
Hammer, GD ;
Korobkin, M ;
Worden, FP .
ENDOCRINE-RELATED CANCER, 2005, 12 (03) :667-680
[25]   Visualizing the acute effects of vascular-targeted therapy in vivo using intravital Microscopy and magnetic resonance imaging:: Correlation with endothelial apoptosis, cytokine induction, and treatment outcome [J].
Seshadri, Mukund ;
Spernyak, Joseph A. ;
Maier, Patricia G. ;
Cheney, Richard T. ;
Mazurchuk, Richard ;
Bellnier, David A. .
NEOPLASIA, 2007, 9 (02) :128-135
[26]   Mitotane levels predict the outcome of patients with adrenocortical carcinoma treated adjuvantly following radical resection [J].
Terzolo, M. ;
Baudin, A. E. ;
Ardito, A. ;
Kroiss, M. ;
Leboulleux, S. ;
Daffara, F. ;
Perotti, P. ;
Feelders, R. A. ;
deVries, J. H. ;
Zaggia, B. ;
De Francia, S. ;
Volante, M. ;
Haak, H. R. ;
Allolio, B. ;
Al Ghuzlan, A. ;
Fassnacht, M. ;
Berruti, A. .
EUROPEAN JOURNAL OF ENDOCRINOLOGY, 2013, 169 (03) :263-270
[27]   Adjuvant mitotane treatment for adrenocortical carcinoma [J].
Terzolo, Massimo ;
Angeli, Alberto ;
Fassnacht, Martin ;
Daffara, Fulvia ;
Tauchmanova, Libuse ;
Conton, Pier Antonio ;
Rossetto, Ruth ;
Buci, Lisa ;
Sperone, Paola ;
Grossrubatscher, Erika ;
Reimondo, Giuseppe ;
Bollito, Enrico ;
Papotti, Mauro ;
Saeger, Wolfgang ;
Hahner, Stefanie ;
Koschker, Ann-Cathrin ;
Arvat, Emanuela ;
Ambrosi, Bruno ;
Loli, Paola ;
Lombardi, Gaetano ;
Mannelli, Massimo ;
Bruzzi, Paolo ;
Mantero, Franco ;
Allolio, Bruno ;
Dogliotti, Luigi ;
Berruti, Alfredo .
NEW ENGLAND JOURNAL OF MEDICINE, 2007, 356 (23) :2372-2380
[28]   Down-regulation of MSH2 expression by an Hsp90 inhibitor enhances pemetrexed-induced cytotoxicity in human non-small-cell lung cancer cells [J].
Tung, Chun-Liang ;
Chiu, Hsien-Chun ;
Jian, Yi-Jun ;
Jian, Yun-Ting ;
Chen, Chien-Yu ;
Syu, Jhan-Jhang ;
Wo, Ting-Yu ;
Huang, Yi-Jhen ;
Tseng, Sheng-Chieh ;
Lin, Yun-Wei .
EXPERIMENTAL CELL RESEARCH, 2014, 322 (02) :345-354
[29]   Perspectives on the combination of radiotherapy and targeted therapy with DNA repair inhibitors in the treatment of pancreatic cancer [J].
Yang, Shih-Hung ;
Kuo, Ting-Chun ;
Wu, Hsu ;
Guo, Jhe-Cyuan ;
Hsu, Chiun ;
Hsu, Chih-Hung ;
Tien, Yu-Wen ;
Yeh, Kun-Huei ;
Cheng, Ann-Lii ;
Kuo, Sung-Hsin .
WORLD JOURNAL OF GASTROENTEROLOGY, 2016, 22 (32) :7275-7288