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Harnessing Apoptosis for Improved Anticancer Gene Therapy

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Harnessing Apoptosis for Improved Anticancer Gene Therapy [CANCER RESEARCH 63, 8563–8572, December 15, 2003] Perspectives in Cancer Research Harnessing Apoptosis for Improved Anticancer Gene Therapy David J. Waxman and Pamela S. Schwartz Division of Cell and Molecular Biology, Department of Biology, Boston University, Boston, Massachusetts Abstract caspases 8 and 9, are activated by two alternative pathways, both of which lead to apoptotic cell death. One pathway is triggered by Advances in our understanding of the mechanisms by which tumor cells cellular stresses that induce changes in mitochondrial function and is detect drug-induced DNA damage leading to apoptotic death have aided primarily associated with the activation of caspase 9 (“intrinsic” in the design of novel, potentially more selective strategies for cancer apoptotic pathway; Refs. 7, 8). The second (“extrinsic”) pathway treatment. Several of these strategies use proapoptotic factors and have 1 shown promise in sensitizing tumor cells to the cytotoxic actions of tradi- activates caspase 8 and proceeds via the formation of a DISC at the tional cancer chemotherapeutic drugs. Although antiapoptotic factors are cell surface, which provides a mechanism for aggregation and auto- generally regarded as poor prognostic factors for successful cancer chem- cleavage (autoactivation) of the caspase (Ref. 9; Fig. 1). As discussed otherapy, strategies that use antiapoptotic factors in combination with below, anticancer drugs with diverse mechanisms of action can acti- suicide or other gene therapies can also be considered. The introduction of vate both apoptotic pathways. Moreover, in both pathways the initi- antiapoptotic factors that act downstream of drug-induced mitochondrial ator caspase cleaves and thereby activates downstream, effector transition delays, but does not block, the ultimate cytotoxic response to caspases, such as caspase 3, caspase 7, and others. This caspase cancer chemotherapeutic drugs that activate a mitochondrial pathway of cascade ultimately leads to proteolytic cleavage of a variety of cellular cell death. Recent studies using the cytochrome P-450 prodrug cyclophos- proteins and induces the broad range of morphological changes that phamide exemplify how the antiapoptotic, caspase-inhibitory baculovirus protein p35 can be combined with P-450 gene-directed enzyme prodrug are characteristic of cells undergoing apoptosis. therapy to prolong localized, intratumoral production of cytotoxic drug metabolites without inducing tumor cell drug resistance. This model may Mitochondrial Cell Death Pathway be adapted to other gene therapies, including those that target death receptor pathways, to maximize the production of soluble, bystander In stress-induced cell death, signals received by mitochondria stim- cytotoxic factors and prodrug metabolites and thereby amplify the ther- ulate mitochondrial membrane permeabilization and release several apeutic response. proapoptotic factors into the cytosol (10–12). Key mitochondrial factors released in this manner include cytochrome c (13), certain Introduction caspases (14), AIF, which induces chromatin condensation and DNA fragmentation (15, 16), and Smac/Diablo, which neutralizes IAP Aberrant regulation of cell growth has traditionally been viewed as proteins and allows caspase activation to proceed (Refs. 17–19; Table the major underlying mechanism for tumor formation; however, it is 1). Mitochondrial release of cytochrome c triggers formation of the becoming increasingly clear that cellular changes that lead to inhibi- apoptosome, an oligomeric, multiprotein complex comprising cyto- tion of apoptosis play an essential role in tumor development (1). chrome c, ATP, caspase 9, and the scaffold protein Apaf-1, which Many cancer chemotherapeutic drugs activate apoptotic mechanisms stimulates/amplifies the activation of caspase 9 and downstream of tumor cell death, suggesting that factors that impair programmed apoptotic events (20, 21). cell death contribute to the resistance of tumor cells to cytotoxic drug Mitochondrial cytochrome c release and apoptosome formation are treatment (2). Elucidation of the apoptotic pathways that are triggered subject to regulation by proteins belonging to the Bcl-2 family, by anticancer therapies is thus an important area of study that may comprising at least 16 family members. The Bcl-2 family includes provide insights into the underlying causes of intrinsic and acquired proapoptotic members, such as Bax and Bid, which promote mito- drug resistance and facilitate the development of novel anticancer chondrial release of proapoptotic factors; and anti-apoptotic members, therapies. This review discusses recent advances in this field and such as Bcl-2, Bcl-X , and Mcl-1, which block factor release (22). A highlights novel therapeutic approaches that use proapoptotic factors L positive correlation between the expression of Bcl-2 and a chemore- to increase responsiveness to classic anticancer drugs, as well as sistant phenotype has been observed in many human tumors, suggest- antiapoptotic factors to optimize suicide and other gene-based thera- ing that Bcl-2 and other family members are important determinants pies for cancer treatment. of the clinical responsiveness to a wide range of anticancer chemo- Role of Caspases in Tumor Cell Death therapeutic agents (22). Many commonly used anticancer drugs induce tumor cell apo- Receptor-mediated Cell Death Pathway ptosis, a process that is mediated by caspases, a ubiquitous family of cysteine proteases that includes both upstream (initiator) and down- Receptor-mediated cell death is initiated by the binding of a death- stream (effector) caspases (3, 4). Caspases are synthesized in an inducing ligand to a cysteine-rich repeat region in the extracellular inactive proform that is activated by proteolytic cleavage at two or domain of a death receptor. This, in turn, leads to activation of more sites. Cleavage at one site generates the large and small subunits trimerized death receptor at the cell surface and activation of caspase of the mature, active protease, whereas cleavage at a second site removes the prodomain (3, 5, 6). The initiator caspases, typically 1 The abbreviations used are: DISC, death-inducing receptor signaling complex; AIF, apoptosis-inducing factor; IAP, inhibitor of apoptosis; Apaf-1, apoptosis protease-activat- ing factor 1; TNF, tumor necrosis factor; TRAIL, TNF-related apoptosis-inducing ligand; Received 6/17/03; revised 9/10/03; accepted 9/25/03. FADD, Fas-associated death domain-containing protein; FLIP, Fas-associated death do- Grant support: NIH Grant CA49248 (to D. J. W.). main-like ICE inhibitory protein; TRAF, TNF receptor-associated factor; NF-␬B, nuclear Requests for reprints: David J. Waxman, Department of Biology, Boston University, factor-␬B; DNA-PK, DNA-dependent protein kinase; GDEPT, gene-directed enzyme 5 Cummington Street, Boston, MA 02215. Fax: (617) 353-7404; E-mail: [email protected]. prodrug therapy; HSV-tk, herpes simplex virus-thymidine kinase. 8563 Downloaded from cancerres.aacrjournals.org on September 24, 2021. © 2003 American Association for Cancer Research. APOPTOTIC FACTORS AND CANCER GENE THERAPY Fig. 1. Intrinsic and extrinsic pathways of apoptotic cell death. The intrinsic pathway of apoptotic cell death is mediated by changes in mitochondrial function, is regulated by Bcl-2 family members, and is associated with the activation of the initiator caspase 9. The extrinsic apoptotic pathway is initiated by the formation of a death-inducing cell surface receptor signaling complex and leads to activation of the initiator caspase 8. In both pathways the activation of an initiator caspase, i.e., caspase 8 or caspase 9, induces the activation of effector caspases. These downstream caspases, in turn, carry out proteolytic cleavage of various cellular proteins and induce the large number of morphological changes that are characteristic of cells undergoing apoptosis. Pro-apoptotic factors are indicated in italic, and antiapoptotic factors are indicated in bold. The antiapoptotic factors Bcl-2 and Bcl-XL inhibit mitochondrial-mediated apoptosis. In type II cells (see text), Bcl-2 can inhibit caspase 8-mediated apoptosis by blocking action of the truncated Bid fragment tBid. IAPs induced downstream of NF-␬B suppress apoptosis by binding directly to and inactivating caspases. IAPs partially inhibit stress-induced apoptosis while fully inhibiting receptor-mediated apoptosis. FLIPs interfere with the recruitment and activation of caspase 8 and thereby inhibit receptor-mediated apoptosis. Decoy receptors bind to death-inducing ligands but do not transmit an intracellular death signal, thereby inhibiting death ligand-induced apoptosis. See text and Table 1 for further details. 8-dependent cell death, as outlined below (Fig. 1). Death receptor ing COOH-terminal death domain of an adaptor protein such as ligands include TNF-␣, Fas ligand, and TRAIL, each associated with FADD (24). The adaptor protein additionally contains a death effector its own specific death receptor. These death receptor-activating li- domain (25) that binds to the NH2 terminus of the caspase 8 prodo- gands are expressed in both membrane-bound and soluble forms and main, thus facilitating DISC formation and proteolytic autoactivation share a homologous 150-amino acid region that interacts with, and of caspase 8. may serve to aggregate, the death receptor (23). Each death receptor Two classes of cells can be distinguished based upon their response contains a cytoplasmic tail “death domain” that binds the correspond-
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