Chemosensitizing Drugs as Immunosensitizing Agents

Even though most advanced malignant tumor cells are resistant to chemotherapeutic drugs and cytotoxic immune cells, in many instances, low levels of the same or different drugs could sensitize resistant tumor cells to immune-mediated apoptosis [33-36]. Sensitization by chemotherapeutic drugs has also been documented in cells that express the drug efflux pump, p-glycoprotein [37]. These observations suggest that the sensitizing property of chemotherapeutic drugs may be distinct from their direct apoptosis-inducing effect. Several proposed mechanisms of immunosensitization have been reported, including transcriptional upregulation of pro-apoptotic proteins and downregulation of anti-apoptotic proteins [38]. The protein expression activity of signaling molecules and regulatory proteins involved in both the receptor-mediated proteins and the mitochondrial pathways have been suggested to be modulated by the drugs (see schematic diagram in Fig. 6.1). Other possible mechanisms for immunosensitization, such as post translational modification and protein translocation, have also been suggested [39]. Other molecular mechanisms of immunosensitization by chemotherapeutic drugs have also been examined and include the following: 1) Upregulation of death receptors. The expression level of death receptors establishes the initial stage for the control of immune-mediated apoptosis. Treatment of certain tumor cells with subtoxic concentrations of chemotherapeutic drugs (e.g. CDDP, ADR, VP16, 5FU, Camptothecin) upregulates the expression of death receptors (Fas, DR4, DR5) while other alternatively spliced variants for soluble receptors or decoy receptors remain unaltered [40-42]. The upregualtion of Fas and DR5 by chemotherapeutic drugs appears to be mediated by a p53-independent mechanism [43]. Recent studies

Immune Resistance

Immune Sensitivity

Fig. 6.1 Tumor Cells Resistance to Killing by Immunotherapy. Schematic diagram illustrating that tumor cells fail to respond to the cytotoxic activity of either antibody or cytotoxic cells. Immune resistance to cytotoxic stimuli by the tumor cells results from multiple mechanisms including hyperactivation of cell survival/anti-apoptotic pathways as well as by dysregulation of gene products that regulate the apoptotic pathways. Intervention by sensitizing agents that can modulate these various anti-apoptotic mechanisms can reverse immune resistance to an immune sensitive phenotype

Immune Resistance

Immune Sensitivity

Fig. 6.1 Tumor Cells Resistance to Killing by Immunotherapy. Schematic diagram illustrating that tumor cells fail to respond to the cytotoxic activity of either antibody or cytotoxic cells. Immune resistance to cytotoxic stimuli by the tumor cells results from multiple mechanisms including hyperactivation of cell survival/anti-apoptotic pathways as well as by dysregulation of gene products that regulate the apoptotic pathways. Intervention by sensitizing agents that can modulate these various anti-apoptotic mechanisms can reverse immune resistance to an immune sensitive phenotype examined the molecular mechanism by which death receptors are dysregulated and the findings revealed that the death receptors are negatively transcribed by the transcription factor Yin Yang 1 (YY1) and its inhibition by chemotherapeutic drugs or by YY1 siRNA sensitized the tumor cells to death ligand-induced apoptosis [36, 44].

6.5.1.1 Upregulation of FADD and Apaf-1 Adaptor Proteins

Following receptor trimerization, the recruitment of FADD protein to intracellular death domains of the death receptor to form DISC is required for initiation of cas-pase activation. The inability to activate the initiator caspase-8 has been proven to be involved in resistance [45]. Upregulation of FADD in drug-mediated sensitization has been reported in several tumor systems [46, 47]. Apaf-1 is the necessary link for mediating the mitochondrial apoptotic pathway [48]. Apaf-1 is upregulated by several chemotherapeutic drugs and sensitizes drugs to death ligands [37].

6.5.1.2 Downregulation of FLIP

FLIP (flice-inhibitory proteins) acts as a dominant negative for caspase-8 and inhibits the death receptor signaling by association with procaspase-8 in the DISC

and prevents the recruitment and activation of caspase-8. Chemotherapeutic drugs sensitize immunoresistant tumor cells by downregulation of FLIP [38, 49].

6.5.1.3 Upregulation of Procaspases

Conventional chemotherapeutic drugs (e.g. etoposide, cisplatin, doxorubiricin and mitomycin) could sensitize tumor cells by selective induction of procaspases-8, 3 and 2 [46, 50]. The drug adriamycin increases the expression of caspase-9 in the drug resistant myeloma cells and sensitizes cells to TRAIL-induced apoptosis [37].

6.5.1.4 Regulation of Bcl-2 Family Proteins

The release of cytochrome c from the mitochondria into the cytoplasm is a crucial and decisive event in the induction of apoptosis [51]. Chemotherapeutic drugs induce the proapoptotic member, Bax via a p53-dependent transcription mechanism [52]. The upregulation of Bax and deregulation of Bcl-xL induced by chemotherapeutic drugs are associated with immunosensitization to death receptor-mediated apoptosis [33, 34].

IAP families of proteins (inhibitors of apoptosis) are a group of anti-apoptotic proteins that function by directly inhibiting certain caspases. The expression of IAP proteins inhibits the execution phase of death receptors-mediated apoptosis in the resistant tumor as they bind and inhibit the active forms of caspase-3 [53] and also bind to caspases-7 and 9 [54]. Several members of IAP proteins have been identified. Overexpressions of IAP proteins have been shown in a variety of chemoresistant tumors. Subtoxic levels of chemotherapeutic drugs have been shown to reduce the activity of IAP family proteins in several tumor cell systems [47, 55, 56].

The above examples have revealed that subtoxic concentrations of chemothera-peutic drugs can elicit a variety of regulatory signals at multiple levels of the apoptotic process. These differ from the direct apoptotic effects induced by drugs. Hence, certain chemotherapeutic drugs can sensitize resistant cancer cells to immune-mediated apoptosis by selectively downregulating anti-apoptotic proteins or upregulating pro-apoptotic proteins involved in the apoptotic pathways.

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