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Study of apoptotic mechanisms induced by all-trans retinoic acid and its 13-cis isomer on cellular lines of human hepato carcinoma Hep3B and HepG2; Estudio de los mecanismos apoptoticos inducidos por el acido retinoico todo-trans y su isomero 13-cis en las lineas celulares de hepatocarcinoma humano Hep3B y HepG2

Thesis/Dissertation:

Abstract

Two cellular lines of liver cancer (Hep3B and HepG2) were incubated during different periods of time with some concentrations of two retinoic acid isomers (ATRA and 13-cis AR) and with 5-fu chemotherapeutic agents, cisplatin and paclitaxel. It was determined if these substances leaded cytotoxicity, apoptosis and if they modified the expression of different genes related to cellular death by apoptosis, in order to explain the hepatocellular carcinoma resistance to these drugs. HepG2 cells showed more resistance than Hep3B cells to 72 hours of treatment, as much ATRA as the 13-cis AR were toxic and produced apoptosis in two cellular lines. This type of cellular death seems to be mediated by a decrease in Bcl-xL concentration in Hep3B cells treated with both retinoids an increase in bax concentration in HepG2 cells treated with 13-cis AR. It were observed 3 and 8 proteolysis of procaspase in Hep3B cells, suggesting extrinsic via activation of the apoptosis, while cellular death in HepG2 cells seems to be independent of caspases. Cisplatin and paclitaxel leaded cytotoxicity to 48 hours of treatment, with significant differences between two cellular lines only in case of paclitaxel. Hep3B cells treated with cisplatin and HepG2 cells treated with paclytaxel suffered apoptosis.  More>>
Authors:
Arce Vargas, Frederick [1] 
  1. Costa Rica
Publication Date:
Jul 01, 2006
Product Type:
Thesis/Dissertation
Resource Relation:
Other Information: TH: Thesis (Magister Scientiae en fisiologia celular); Figs., tabs., refs
Subject:
62 RADIOLOGY AND NUCLEAR MEDICINE; ANTIMITOTIC DRUGS; APOPTOSIS; BIOCHEMISTRY; CELL DIFFERENTIATION; CHEMOTHERAPY; COMBINED THERAPY; EXPERIMENTAL DATA; ISOMERS; LIPOSOMES; LIVER; MOLECULAR STRUCTURE; NEOPLASMS; RETINOIC ACID
OSTI ID:
20997614
Research Organizations:
Universidad de Costa Rica, Sistema de Estudios de Posgrado en Ciencias Biomedicas (Costa Rica)
Country of Origin:
Costa Rica
Language:
Spanish
Other Identifying Numbers:
TRN: CR0800002022099
Availability:
Available from Biblioteca Luis Demetrio Tinoco, Universidad de Costa Rica
Submitting Site:
INIS
Size:
95 pages
Announcement Date:
Apr 11, 2008

Thesis/Dissertation:

Citation Formats

Arce Vargas, Frederick. Study of apoptotic mechanisms induced by all-trans retinoic acid and its 13-cis isomer on cellular lines of human hepato carcinoma Hep3B and HepG2; Estudio de los mecanismos apoptoticos inducidos por el acido retinoico todo-trans y su isomero 13-cis en las lineas celulares de hepatocarcinoma humano Hep3B y HepG2. Costa Rica: N. p., 2006. Web.
Arce Vargas, Frederick. Study of apoptotic mechanisms induced by all-trans retinoic acid and its 13-cis isomer on cellular lines of human hepato carcinoma Hep3B and HepG2; Estudio de los mecanismos apoptoticos inducidos por el acido retinoico todo-trans y su isomero 13-cis en las lineas celulares de hepatocarcinoma humano Hep3B y HepG2. Costa Rica.
Arce Vargas, Frederick. 2006. "Study of apoptotic mechanisms induced by all-trans retinoic acid and its 13-cis isomer on cellular lines of human hepato carcinoma Hep3B and HepG2; Estudio de los mecanismos apoptoticos inducidos por el acido retinoico todo-trans y su isomero 13-cis en las lineas celulares de hepatocarcinoma humano Hep3B y HepG2." Costa Rica.
@misc{etde_20997614,
title = {Study of apoptotic mechanisms induced by all-trans retinoic acid and its 13-cis isomer on cellular lines of human hepato carcinoma Hep3B and HepG2; Estudio de los mecanismos apoptoticos inducidos por el acido retinoico todo-trans y su isomero 13-cis en las lineas celulares de hepatocarcinoma humano Hep3B y HepG2}
author = {Arce Vargas, Frederick}
abstractNote = {Two cellular lines of liver cancer (Hep3B and HepG2) were incubated during different periods of time with some concentrations of two retinoic acid isomers (ATRA and 13-cis AR) and with 5-fu chemotherapeutic agents, cisplatin and paclitaxel. It was determined if these substances leaded cytotoxicity, apoptosis and if they modified the expression of different genes related to cellular death by apoptosis, in order to explain the hepatocellular carcinoma resistance to these drugs. HepG2 cells showed more resistance than Hep3B cells to 72 hours of treatment, as much ATRA as the 13-cis AR were toxic and produced apoptosis in two cellular lines. This type of cellular death seems to be mediated by a decrease in Bcl-xL concentration in Hep3B cells treated with both retinoids an increase in bax concentration in HepG2 cells treated with 13-cis AR. It were observed 3 and 8 proteolysis of procaspase in Hep3B cells, suggesting extrinsic via activation of the apoptosis, while cellular death in HepG2 cells seems to be independent of caspases. Cisplatin and paclitaxel leaded cytotoxicity to 48 hours of treatment, with significant differences between two cellular lines only in case of paclitaxel. Hep3B cells treated with cisplatin and HepG2 cells treated with paclytaxel suffered apoptosis. 5-FU produced toxicity only when it was used to high concentrations and the mechanism of cellular death induced by this agent seems to be primarily necrosis in Hep3B cells and apoptosis in HepG2. There was decrease in the Bcl-xL concentration in two cellular lines when it was treated with cisplatin and in HepG2 cells treated with 5-FU. Bax concentration there no was modified with no treatment. Activation of the 3 caspases seems to happen only in HepG2 cells with 5-FU and paclytaxel. These two agents, also, decreased the survivin concentration of HepG2 cells. Treatments of the three drugs produced an increase in the expression of this gen in Hep3B cells, which might explain partially the resistance of these cells to different chemotherapeutic agents. Survivin might decrease the answer of treatment by to be anti-apoptotic and even to change the apoptosis by other forms of cellular death (necrosis, mitotic catastrophe, etc.) doing that therapy be less efficient. Hep3B cells were sensitized with ATRA before to be treated with 5-FU and it was observed a more cytotoxicity than when every drug was used separately. Also there were required concentrations lower of both agents to produce cellular death. This effect didn't see with HepG2 cells. Although retinoids seem to be promising in the hepato carcinoma treatment, it must do more studies to improve the bioavailability and to decrease the unspecific toxicity of these drugs, including combinations with other agents, use of liposomes or synthesis of compounds with effects more selective that might be even directed to certain specific routes of cellular death. (author) [Spanish] Dos lineas celulares de cancer de higado (Hep3B and HepG2) se incubaron durante diferentes periodos de tiempo con varias concentraciones de dos isomeros del acido retinoico (ATRA y 13-cis AR) y con los agentes quimioterapeuticos 5-FU, cisplatino y paclitaxel. Se determino si estas sustancias inducian citotoxicidad, apoptosis y si modificaban la expresion de diferentes genes relacionados con la muerte celular por apoptosis, en parte para poder explicar la resistencia del carcinoma hepatocelular a estas drogas. Las celulas HepG2 mostraron mayor resistencia que las celulas Hep3B a las 72 horas de tratamiento, tanto el ATRA como el 13-cis AR fueron toxicos. Tambien se demostro que producian apoptosis en las dos lineas celulares. Este tipo de muerte celular parece estar mediada por una disminucion en la concentracion de Bcl-xL en las celulas Hep3B tratadas con ambos retinoides y un aumento en la concentracion de Bax en las celulas HepG2 tratadas con 13-cis AR. Se observo proteolisis de procaspasas 3 y 8 en las celulas Hep3B, sugiriendo activacion de la via extrinseca de la apoptosis, mientras que la muerte celular en las celuals HepG2 parece ser independiente de caspasas. El cisplatino y el paclitaxel indujeron citotoxicidad a las 48 horas de tratamiento, con diferencias significativas entre las dos lineas celulares solo en el caso del paclitaxel. Las celulas Hep3B tratadas con cisplatino y las celulas HepG2 tratadas con paclitaxel sufrieron apoptosis. El 5-FU solo produjo toxicidad cuando se empleo a altas concentraciones y el mecanismo de muerte celular inducido por este agente parece ser primariamente necrosis en las celulas Hep3B y apoptosis en las HepG2. Hubo disminucion en la concentracion de Bcl-xL en las dos lineas celulares cuando se trataron con cisplatino y en las celulas HepG2 tratadas con 5-FU. La concentracion de bax no se modifico con ningun tratamiento. La activacion de la caspasa 3 parece ocurrir solo en las celulas HepG2 tratadas con 5-FU y paclitaxel. Estos dos agentes tambien disminuyeron la concentracion de survivina en las celulas HepG2. Los tratamientos con las tres drogas produjeron un aumento en la expresion de este gen en las celulas Hep3B, lo cual podria explicar parcialmente la resistencia de estas celulas a los diferentes agentes quimioterapeuticos. La survivina podria disminuir la respuesta al tratamiento al ser anti-apoptotica e incluso cambiar la apoptosis por otras formas de muerte celular (necrosis, catastrofe mitotica, etc.), haciendo que la terapia sea menos eficiente. Las celulas Hep3B fueron sensibilizadas con ATRA antes de ser tratadas con 5-FU y se observo una mayor citotoxicidad que cuando se empleo cada droga por separado. Tambien se requirieron concentraciones mas bajas de ambos agentes para producir muerte celular. Este efecto no se vio con las celulas HepG2. Aunque los retinoides parecen ser prometedores en el tratamiento del hepatocarcinoma, se deben realizar mas estudios para mejorar la biodisponibilidad y disminuir la toxicidad inespecifica de estas drogas, incluyendo combinaciones con otros agentes, empleo de liposomas o sintesis de compuestos con efectos mas selectivos, que podrian estar incluso dirigidos a ciertas vias especificas de muerte celular. (autor)}
place = {Costa Rica}
year = {2006}
month = {Jul}
}