Downregulation of mutant p53 and severe growth inhibition mediated by antisense-oligonucleotides in pancreatic tumor cells indicate a ‘gain of function’—Type of mutation

1995 ◽  
Vol 121 (S1) ◽  
pp. A1-A1
Author(s):  
A. Fiedler ◽  
Y. Franke ◽  
B. Büsing ◽  
C. Röder ◽  
J. Lüttges ◽  
...  
Keyword(s):  
Growth Inhibition ◽  
Tumor Cells ◽  
Antisense Oligonucleotides ◽  
Pancreatic Tumor ◽  
Mutant P53 ◽  
Gain Of Function ◽  
Function Type ◽  
Severe Growth

scholarly journals Semi-Synthesis of Small Molecules of Aminocarbazoles: Tumor Growth Inhibition and Potential Impact on p53

Molecules ◽  
2021 ◽  
Vol 26 (6) ◽  
pp. 1637
Author(s):  
Solida Long ◽  
Joana B. Loureiro ◽  
Carla Carvalho ◽  
Luís Gales ◽  
Lucília Saraiva ◽  
...  
Keyword(s):  
Growth Inhibition ◽  
Small Molecules ◽  
Tumor Cells ◽  
Mutant P53 ◽  
Wild Type ◽  
Naturally Occurring ◽  
Growth Inhibitory ◽  
Growth Inhibitory Activity ◽  
Amino Derivatives ◽  
Carbazole Alkaloids

The tumor suppressor p53 is inactivated by mutation in approximately 50% of human cancers. Small molecules that bind and stabilize those mutants may represent effective anticancer drugs. Herein, we report the tumor cell growth inhibitory activity of carbazole alkaloids and amino derivatives, as well as their potential activation of p53. Twelve aminocarbazole alkaloids were semi-synthesized from heptaphylline (1), 7-methoxy heptaphylline (2), and 7-methoxymukonal (3), isolated from Clausena harmandiana, using a reductive amination protocol. Naturally-occurring carbazoles 1–3 and their amino derivatives were evaluated for their potential effect on wild-type and mutant p53 activity using a yeast screening assay and on human tumor cell lines. Naturally-occurring carbazoles 1–3 showed the most potent growth inhibitory effects on wild-type p53-expressing cells, being heptaphylline (1) the most promising in all the investigated cell lines. However, compound 1 also showed growth inhibition against non-tumor cells. Conversely, semi-synthetic aminocarbazole 1d showed an interesting growth inhibitory activity in tumor cells expressing both wild-type and mutant p53, exhibiting low growth inhibition on non-tumor cells. The yeast assay showed a potential reactivation of mutant p53 by heptaphylline derivatives, including compound 1d. The results obtained indicate that carbazole alkaloids may represent a promising starting point to search for new mutp53-reactivating agents with promising applications in cancer therapy.

scholarly journals Mutant p53 Sequestration of the MDM2 Acidic Domain Inhibits E3 Ligase Activity

2018 ◽  
Vol 39 (4) ◽  
Author(s):  
Leixiang Yang ◽  
Tanjing Song ◽  
Qian Cheng ◽  
Lihong Chen ◽  
Jiandong Chen
Keyword(s):  
Tumor Cells ◽  
Recent Work ◽  
Intramolecular Interaction ◽  
E3 Ligase ◽  
Mutant P53 ◽  
Wild Type ◽  
Gain Of Function ◽  
Core Domain ◽  
Acidic Domain ◽  
Wild Type P53

ABSTRACT Missense p53 mutants often accumulate in tumors and drive progression through gain of function. MDM2 efficiently degrades wild-type p53 but fails to degrade mutant p53 in tumor cells. Previous studies revealed that mutant p53 inhibits MDM2 autoubiquitination, suggesting that the interaction inhibits MDM2 E3 activity. Recent work showed that MDM2 E3 activity is stimulated by intramolecular interaction between the RING and acidic domains. Here, we show that in the mutant p53-MDM2 complex, the mutant p53 core domain binds to the MDM2 acidic domain with significantly higher avidity than wild-type p53. The mutant p53-MDM2 complex is deficient in catalyzing ubiquitin release from the activated E2 conjugating enzyme. An MDM2 construct with extra copies of the acidic domain is resistant to inhibition by mutant p53 and efficiently promotes mutant p53 ubiquitination and degradation. The results suggest that mutant p53 interferes with the intramolecular autoactivation mechanism of MDM2, contributing to reduced ubiquitination and increased accumulation in tumor cells.

Growth inhibition of pancreatic tumor cells by modified antisense oligodeoxynucleotides

1998 ◽  
Vol 383 (3-4) ◽  
pp. 269-275 ◽  
Author(s):  
Alexander Fiedler ◽  
Christoph Knorre ◽  
Yvonne Franke ◽  
Doris Henne-Bruns ◽  
Bernd Kremer ◽  
...  
Keyword(s):  
Growth Inhibition ◽  
Tumor Cells ◽  
Pancreatic Tumor ◽  
Antisense Oligodeoxynucleotides

scholarly journals Gain-of-function mutant p53 downregulates miR-223 contributing to chemoresistance of cultured tumor cells

Oncogene ◽  
2013 ◽  
Vol 33 (12) ◽  
pp. 1601-1608 ◽  
Author(s):  
S Masciarelli ◽  
G Fontemaggi ◽  
S Di Agostino ◽  
S Donzelli ◽  
E Carcarino ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Mutant P53 ◽  
Gain Of Function ◽  
Cultured Tumor Cells

S2001 Restoration of 15-Lipoxygenase Expression in Pancreatic Tumor Cells Leads to Growth Inhibition and Is Associated with Upregulation of Tumorsuppressor p53

2009 ◽  
Vol 136 (5) ◽  
pp. A-310
Author(s):  
Timo Kehl ◽  
René Hennig ◽  
Frank Bergmann ◽  
Gerhardt Fürstenberger ◽  
Helmut Friess ◽  
...  
Keyword(s):  
Growth Inhibition ◽  
Tumor Cells ◽  
Pancreatic Tumor

COMPARATIVE STUDY OF THE EFFECTS OF NOS INHIBITOR T1023 AND BEVACIZUMABUM ON GROWTH AND MORPHOLOGY OF LEWIS LUNG CARCINOMA

2019 ◽  
pp. 89-98
Author(s):  
М.В. Филимонова ◽  
В.В. Южаков ◽  
А.С. Филимонов ◽  
В.М. Макарчук ◽  
Л.Н. Бандурко ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Growth Inhibition ◽  
Tumor Cells ◽  
Lung Carcinoma ◽  
Comparative Studies ◽  
Lewis Lung Carcinoma ◽  
Lewis Lung ◽  
Vegf Inhibitor ◽  
Nos Inhibitor ◽  
Experimental Group

Цель исследования - изучение механизмов противоопухолевой активности ингибитора NOS Т1023 и оценка перспективности его дальнейшей разработки. Методика. В качестве опухолевой модели использована эпидермоидная КЛЛ, штамм которой получен из банка опухолевых материалов ФГБУ РОНЦ им. Н.Н. Блохина и поддерживался на самцах мышей C57BL6j. КЛЛ трансплантировали самцам мышей F1 (CBA´C57BL6j) путем подкожного введения 1,5×106 клеток карциномы в 0,1 мл суспензии на основе среды 199 в область латеральной поверхности правого бедра. Для сравнительной оценки противоопухолевой эффективности использовали ингибитор NOS под шифром Т1023, синтезированный в лаборатории радиационной фармакологии МРНЦ им. А.Ф. Цыба, и VEGF-ингибитор бевацизумаб (БВЗ). Животным первой опытной группы ежедневно, со 2 по 20 сутки вводили соединение Т1023 (60 мг/кг, в/б); второй опытной группы - трижды, на 2, 5 и 10 сут вводили БВЗ (12 мг/кг, в/б); третьей опытной группы - по этим схемам и в таких же дозах вводили и Т1023, и БВЗ (при комбинированном применении Т1023 вводили через 4 ч после введения БВЗ). Контрольным животным в качестве плацебо со 2 по 20 сутки вводили 0,9% раствор натрия хлорида (0,2 мл, в/б). Противоопухолевые эффекты оценивали, сравнивая размеры опухолевых узлов, длительность задержки роста и индекс торможения роста опухоли у контрольных и опытных животных. Гистологические методы исследования включали иммуноокрашивание на PCNA, CD31, пимонидазол и морфометрический анализ микроскопических изображений. Результаты сравнительных исследований показали, что соединение Т1023 и VEGF-ингибитор бевацизумаб (БВЗ) оказывают однонаправленное влияние на карциному легких Льюис (КЛЛ), сопровождающееся торможением роста и подавлением метастазирования неоплазии. Воздействие и Т1023, и БВЗ вызывало снижение содержания сосудов в перитуморальных зонах и в «горячих точках» ангиогенеза, усиливало гипоксию паренхимы КЛЛ и стимулировало апоптоз опухолевых клеток. При комбинированном применении Т1023 и БВЗ их антинеопластическая эффективность в отношении ингибирования ангиогенеза и девитализации опухолевых клеток соответствовала аддитивному действию. Заключение. Результаты позволяют предполагать, что основой противоопухолевой активности Т1023 является антиангиогенное действие и свидетельствуют о перспективности применения ингибиторов NOS в ангиостатической терапии солидных злокачественных новообразований в сочетании с имеющимися антинеоваскулярными средствами. The aim. Study of mechanisms of NOS inhibitor T1023 antitumor activity and estimation of its prospects for further development. Methods. Epidermoid Lewis lung carcinoma (LLC) from N.N. Blokhin NMRCO bank of tumor materials was used as a tumor model. Maintenance of tumor cell culture was provided by intramuscular injection of tumor cells suspension to C57BL6j mice every 14 days. Then LLC cells were transplanted to male F1 mice (CBA´C57BL6j) by subcutaneous injection of 1,5×106 cells in 0,1 ml of 199 medium into the lateral surface of the right hip. Comparative studies of antitumor efficacy were carried out using NOS inhibitor T1023, synthesized in the laboratory of radiation pharmacology of A.F. Tsyb MRRC, and VEGF inhibitor Bevacizumab (BVZ). Mice from the first experimental group were injected intraperitoneally (ip) with compound T1023 at dose 60 mg / kg from day 2 to 20; animals from the second experimental group were treated with BVZ at dose 12 mg / kg ip at days 2, 5 and 10; the third experimental group received T1023 in combination with BVZ according to these schemes and at the same doses (T1023 was administered 4 hours after administration of BVZ). Mice from the control group received 0,9% sodium chloride solution (0,2 ml, ip) as a placebo daily from 2 to 20 days. Antitumor effects were assessed by comparing the tumor size, duration of tumor growth delay and the index of tumor growth inhibition in control and experimental groups. Histological examination methods included immunostaining on PCNA, CD31, pimonidazole and morphometric analysis of microscopic images. Results. Comparative studies have shown that compound T1023 and VEGF inhibitor Bevacizumab (BVZ) have unidirectional effects on Lewis lung carcinoma (LLC), accompanied by growth inhibition and suppression of metastasis of neoplasia. The effect of both T1023 and BVZ caused a decrease in vascular content in the peritumoral zones and in the “hot spots” of angiogenesis, increased the hypoxia in the LLC parenchyma, and stimulated apoptosis of tumor cells. The combined use of T1023 and BVZ, caused the antineoplastic efficacy against inhibition of angiogenesis and devitalization of tumor cells which was estimated as additive effect. Conclusion. The results suggest that the basis of antitumor activity of T1023 is the anti-angiogenic effect and indicate the prospects of using NOS inhibitors in the angiostatic therapy of solid malignant neoplasms in combination with available anti-neovascular agents.

Sign in / Sign up

Export Citation Format

Share Document