Phytochemicals: A Multitargeted Approach to Gynecologic Cancer Therapy
Figure 1
A hypothetical model of chemoresistance in human ovarian cancer cells. In a chemosensitive ovarian cancer cell (a), cisplatin activates p53, leading to upregulation of proteins promoting cell cycle arrest, such as p21, and of proapoptotic proteins such as Bax and Fas. This activates both the intrinsic (mitochondrial) and the extrinsic (death-receptor) apoptotic pathways, the overall result of which is the activation of the execution caspase-3 (and caspase-7, not shown). In these cells, cell survival mediators such as Xiap, Akt, and Flip (shown in red) are downregulated or are in their inactive state. In chemoresistant cells (b), increased p53 ubiquitination by MDM2 results in the maintenance of low levels of p53, despite the presence of cisplatin. Moreover, cisplatin fails to downregulate Xiap, thereby maintaining an active state of the PI3K/Akt pathway. In addition, binding of TNFR2 by TNFα leads to upregulation of FLIP through the NF-κB pathway, thus inhibiting the proapoptotic actions of the cytokine through TNFR1. Overall, as a consequence of a failure to activate the caspase cascade in response to the chemotherapeutic agent, these cells have lost their capacity to undergo apoptosis and thus became chemoresistant. Taken from [15].
