الفهرس 
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Abstract
HCC is the most common type of primary liver cancer in adults and is the most common cause of death in people with cirrhosis. The detailed molecular mechanism of hepatocarcinogenesis is still not well known.
Cisplatin (CDDP) is one of the best and first metal-based chemotherapeutic drugs. It is used for wide range of solid cancers such as testicular, ovarian, bladder, lung, cervical, head and neck cancer, gastric cancer and some other cancers. from cisplatin limitations, are the normal tissue cytotoxicity and cancer cells chemoresistance. Therefore, combination therapy of cisplatin with other drug has been highly recommended aiming to overcome its serious side effects.
TQ has promising anticancer activity in vitro and in vivo models. It proved to be effective against several types of cancer cell lines in which the classical hallmark of apoptosis such as chromatin condensation, translocation of phosphatidyl serine across the plasma membrane, and DNA fragmentation have been documented in TQ-treated cells.
The aim of the present study is to assess the effect of Cisplatin and/or thymoquinone on HCC induced experimentally in rats, and to study their possible mechanism of action through assessment the level of miRNA-192, clarifying its possible association with the TGF-β taking in consideration the role of endoplasmic stress markers.
Fifty male adult albino rats were enrolled in this study and equally divided as follows:
1) group I: vehicle healthy control rats.
2) group II: Experimental HCC (diseased control).
3) group III: HCC rats received cisplatin.
4) group IV: HCC rats received TQ.
5) group V: HCC rats received both cisplatin and TQ.
All groups were subjected to:
1. Blood samples were collected from rats of all groups for assessment of AST, ALT, Bilirubin and AFP.
2. At the planned time, animals were euthanized, and the hepatic tissues were examined for:
a) Gene expression of GRP78, CHOP, E-cadherin, microRNA-192 and caspase 3 by qRT-PCR.
b) Estimation of SOD and MDA by colorimetry.
c) Estimation of TGF-beta by ELISA.
d) Protein expression of NFκB by western blot.
e) Histopathological examination.
Results revealed that:
1. Serum levels of ALT, AST, bilirubin ,AFP and TGF-β1 were significantly decreased in all treated groups with more suppressive effect in the group treated with both TQ and cisplatin.
2. Hepatic tissue levels of MDA significantly decreased in HCC+TQ group & combined group while SOD levels was significantly higher in HCC+TQ group & combined group.
3. Regarding ER stress proteins GRP-78 was significantly higher in HCC group but it significantly decreased in HCC+TQ group & combined group as compared to HCC group. CHOP was increased in all treated groups significantly with HCC+TQ group & combined group.
4. Caspase 3, E-cadherin and microRNA-192 levels were significantly increased in all treated groups particularly with HCC+TQ group & combined group.
5. NF-KB level was significantly higher in HCC group but it significantly decreased in HCC+TQ group & combined group as compared to HCC group.
6. Histopathological examination from HCC group revealed dysplastic cirrhotic nodules and solid areas of neoplasia. Administration of TQ or Cisplatin into induced HCC rats improved the histopathological picture with residual pathology, while administration of both TQ and Cisplatin showed restoration of liver parenchyma with minimal nuclear atypia.
In conclusion, TQ and/or Cisplatin might have therapeutic effect on HCC, possibly through balancing oxido/reductive state and affecting the endoplasmic stress proteins, and apoptosis.