الفهرس 
IntroductionOnly 14 pages are availabe for public view
 |  | from | 32 |  |  |
| | | from | 32 | | |
Abstract
The drastic conditions of tumor microenviroment as hypoxia and acidosis plays a critical role in phenotypic selection and increased the aggressiveness of cancer cells survived from these conditions. However, the manipulation of the molecular mechanisms acquired by cancer cells to withstand these conditions is an attractive therapeutic approach. Among different approaches of targeting the tumor microenviroment is interfering with the function of the pH preserving transporters which protect cancer cells from the intracellular acidification. Recently, the role of CA in controlling the pH gradient of tumor cells and the lethal results of its inhibition was clarified.
The current study evaluated the antitumor activity of acetazolamide, brinzolamide and dorzolamide against both MCF-7 cell line and EAC solid tumor. Moreover, the current work evaluated the possible antiangiogenic activity of dorzolamide and its combination outcome with the standard chemotherapeutic agents cisplatin, chlorambucil and mitomycin C. Furthermore, the current work determined the role of TXNIP in mediating the antitumor effect of dorzolamide and mitomycin C against EAC solid tumor.
Ehrlich Ascites Carcinoma was proven to be liable to the antitumor activity of CA inhibitors. However, dorzolamide showed a superior antitumor activity over other inhibitors used in the current study as indicated from its IC50 against MCF-7 cell line in vitro and its effect on the solid tumor weight of EAC in vivo. However, dorzolamide did not show any influence on tumor angiogenesis as indicated from its negative effect on the expression of the angiogenic marker CD31.
Furthermore, dorzolamide showed a synergistic outcome upon combination with chlorambucil and to a greater extent when combined with mitomycin; while a strong antagonism resulted from its combination with cisplatin against EAC solid tumors.
Moreover, the investigation of the molecular mechanisms underlying the antitumor activity of dorzolamide, mitomycin C and their combination revealed that both drugs shared the ability of increasing the TXNIP-p53-bax axis and consequently activating the intrinsic apoptotic pathway. In addition, their antiproliferative activity indicated from the reduced proliferative nuclei stained with Ki-67. Furthermore, the combination of dorzolamide and mitomycin C resulted in a further increase of the proapoptotic, anti-proliferative effects and the synergistic outcome of their combination upon increasing the dose of dorzolamide.
In conclusion, the current work demonstrated the liability of EAC cell line to the antitumor activity of CA inhibitors. Meanwhile, the current study demonstrated that the antitumor activity of dorzolamide was partly attributed to both TXNIP dependent tumor suppression pathways in addition to its ability to down regulate the level of bcl-2. Moreover, the current work proved the ability of mitomycin C to upregulate p53, bax; besides activating the intrinsic apoptotic pathway in the EAC solid tumor, which was described earlier in another tumor models.
Moreover, the current study suggested TXNIP as an emerging mediator of mitomycin C antitumor activity which could act apically to the rest of molecular mediators of its tumor suppressor effect. Finally, the present study proved that dorzolamide synergized the antitumor activity of mitomycin C against EAC solid tumor grown in vivo.