After completing this course, the reader will be able to:1. Describe the pathways involved in the natural resistance of cancer cells to cytotoxic insults including radio-/chemotherapy.2. Explain autophagic cell death as a potent alternative tumor-suppressing mechanism.3. Identify the common targets in apoptosis and autophagy resistance pathways and the surrogate markers that could be used in clinical practice for proautophagic therapy.4. Discuss the rationale for incorporating endoplasmic reticulum stress inhibitors as adjuvant chemotherapies against apoptosis-resistant cancers.Access and take the CME test online and receive 1 AMA PRA Category 1 Credit ™ at CME.TheOncologist.com CME CME
ABSTRACTThe therapeutic goal of cancer treatment has been to trigger tumor-selective cell death. Although cell death can be achieved not only by apoptosis (type I programmed cell death) but also by necrosis, mitotic catastrophe, and autophagy, drugs inducing apoptosis remain the main chemotherapeutic agents in medical oncology. However, cancer cells in their relentless drive to survive, hijack cell processes, resulting in apoptosis resistance, which underlies not only tumorigenesis but also the inherent resistance of certain cancers to radiotherapy and chemotherapy. Unlike apoptosis, which is a caspase-dependent process characterized by nuclear condensation and fragmentation, autophagic cell death is a caspase-independent process characterized by the accumulation of autophagic vacuoles in the cytoplasm accompanied by extensive degradation of the Golgi apparatus, the polyribosomes, and the endoplasmic reticulum, which precedes the destruction of the nucleus. Another apoptosis target generating great excitement is X-linked inhibitor of apoptosis (XIAP) [3], which binds to three key caspases, preventing them from activating and killing cancer cells. However, like Bcl-2 inhibitors, XIAP inhibitors must block a protein-protein interaction. Smac, an endogenous protein that is released from mitochondria, binds with XIAP and inactivates it, triggering apoptosis [11]. This discovery raised the possibility of Smac mimetics to treat cancer [11]. Most companies are designing drugs targeting one of the two XIAP-caspase binding domains in order to mimic Smac's full caspase activation function and ensure that apoptosis takes place. Small-molecule XIAP inhibitors are in preclinical evaluation. All three approaches, Bcl-2 inhibitors, TRAIL modulators, and Smac mimetics, have thus yet to be clinically validated.
NATURAL RESISTANCE OF CANCER CELLS TO APOPTOSISResistance to apoptosis is considered to be a characteristic of many diverse cancer cells [3]. Defects in apoptosis underlie not only tumorigenesis but also resistance to cancer treatments [3]. Furthermore, the inherent resistance of cancer cells to radiotherapy and chemotherapy is contributed to by changes at genomic, transcriptional, and post-transcriptional levels of proteins and protein kinases and their transcriptional factor effectors [3] (Fig. 1). The phosphatase and tensin homologue de...