Proautophagic Drugs: A Novel Means to Combat Apoptosis-Resistant Cancers, with a Special Emphasis on Glioblastomas

Abstract

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...

2-Hydroxyoleate, a nontoxic membrane binding anticancer drug, induces glioma cell differentiation and autophagy

“…Autophagy is an alternative program of cell death that may overcome the resistance of many cancers (e.g., glioma) to enter the apoptotic program (39). In this context, we detected that 2OHOA-induced autophagy in SF767 cells (Fig.…”

microRNA-17 regulates the expression of ATG7 and modulates the autophagy process, improving the sensitivity to temozolomide and low-dose ionizing radiation treatments in human glioblastoma cells

“…18,25,26 In addition, the induction of autophagic cell death (type II cell death) by pro-autophagic drugs is an alternative and emerging concept to trigger glioma cell death and to exploit caspase-independent programmed cell death pathways for the development of novel glioma therapies. 27 A variety of chemical or physical treatments, including rapamycin (mTOR inhibitor), radiation, arsenic trioxide, ceramide, temozolomide, dopamine, endostatin, the histone deacetylase (HDAC) inhibitors butyrate and suberoylanilide hydroxamic acid, neodymium oxide, the chemotherapeutic vitamin D analog EB1089, saponins, and resveratrol, have been reported to induce autophagy in vitro and in vivo in certain cancer cells. 28 Notably, temozolomide brings significant therapeutic benefits in glioblastoma treatment and its cytotoxic activity is exerted through pro-autophagic processes.…”

N-Aryl-N′-(chroman-4-yl)ureas and thioureas display in vitro anticancer activity and selectivity on apoptosis-resistant glioblastoma cells: Screening, synthesis of simplified derivatives, and structure–activity relationship analysis

“…High-grade (anaplastic astrocytoma and glioblastoma (GBM)) glioma patients are associated with dismal prognoses because of: (i) the marked diffuse invasion of glioma cells into the brain parenchyma [1,2], rendering elusive complete surgical resection [3], and (ii) the intrinsic resistance of glioma cells to pro-apoptotic stimuli [2], thus to conventional radiotherapy and chemotherapy [4]. The standard treatment for high-grade glioma patients consists of maximal surgical resection followed by radiotherapy and chemotherapy with temozolomide [4,5].…”