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...
With an overall 5 year survival rate as low as 15% for non-small cell lung cancer (NSCLC), even with surgical intervention and the use of newer molecules in adjuvant chemotherapy, there is an urgent need for new biological targets and associated novel anti-cancer agents. The present study was undertaken to evaluate the potential of the Na(+)/K(+)-ATPase alpha1 subunit as a novel target in NSCLC and revealed that alpha1 expression is markedly higher in a significant proportion of NSCLC clinical samples compared to normal lung tissue. Furthermore, reduction in alpha1 expression in A549 NSCLC cells by anti-alpha1 siRNA resulted in markedly impaired proliferation and migration of these cancer cells. Finally, of three cardenolides investigated, UNBS1450, which is known to bind to Na(+)/K(+)-ATPase and displays potent anti-tumour activity in vivo in experimental models of human NSCLCs, is the most potent inhibitor of Na(+)/K(+)-ATPase isozymes (alpha1beta1, alpha2beta1 and alpha3beta1), most strikingly of alpha1beta1. This was reflected in the compound's more potent anti-proliferative activity in all NSCLC cell lines evaluated (A549, Cal-12T, NCI-H727 and A427); the first three of which over-express alpha1. The marked impairment in A549 NSCLC cell proliferation and migration, and resulting similar morphology following anti-alpha1 siRNA or UNBS1450 treatment, was associated with features of abnormal cytokinesis, mediated in the case of UNBS1450 by disorganization of the actin cytoskeleton. Collectively these data strongly suggest that targeting the Na(+)/K(+)-ATPase alpha1 using specific cardenolides could represent a novel means to combat certain NSCLCs.
The use of cardenolides like ouabain, digitoxin, or oleandrin has been reported previously many times as a means of potentially combating human refractory prostate cancer by inducing apoptosis through an increase in intracellular calcium concentrations. The aims of the current study were to investigate if part of the antitumor effects mediated by cardenolides concerned disorganization of nucleolar structure and whether this was further associated with a marked decrease in c-Myc expression. Accordingly, the antitumor activity of a novel hemisynthetic cardenolide [1R,3aS,3bR, 5aS,6aR,7aS,9R,12aR,13aR,15aR]-3a,11a-dihydroxy13a-(hydroxymethyl)-9,15a-dimethyl-1-(5-oxo-2,5-dihydrofuran-3-yl)icosahydro-1H,4 ¶H-spiro[cyclopenta [7,8] phenanthro [2,3-b ]pyrano[3,2-e][1,4]dioxine-11,2 ¶-[1,3] thiazolidin]-4 ¶-one (UNBS1450)] was compared with that of classic cardenolides and reference anticancer agents in prostate cancer cell lines in vitro and in vivo following s.c. and orthotopic prostate cancer cell grafting into mice. The present study indicates that UNBS1450 markedly decreases the in vitro viability/proliferation of human prostate cancer cell lines but not of normal cells. The induced effects are not linked to an increase in intracellular calcium concentrations and subsequent induction of apoptosis. Rather, they appear to relate to the compound's capacity to disorganize nucleolar structure and function (through an impairment of cyclin-dependent kinase and c-Myc expression and related signaling pathways; paralleled by the disorganization of cancer cellspecific perinucleolar bodies as revealed by disruption of Sam68). This nonapoptotic cancer cell death mediated by severe nucleolar targeting and down-regulation of c-Myc expression is a completely new cardenolide-induced mechanism of antitumor action. [Mol Cancer Ther 2008; 7(5):1285 -96]
The third in this series of papers describes our further progress into the discovery of a potent and selective endothelin A (ETA) receptor antagonist for the potential treatment of diseases in which a pathophysiological role for endothelin has been implicated. These include hypertension, ischemic diseases, and atherosclerosis. In earlier publications we have outlined the discovery and structure-activity relations of two moderately potent series of nonpeptide ETA receptor antagonists. In this paper, we describe how a pharmacophore model for ETA receptor binding was developed which enabled these two series of compounds to be merged into a single class of 4-phenoxybutanoic acid derivatives. The subsequent optimization of in vitro activity against the ETA receptor led to the discovery of (R)-4-[2-cyano-5-(3-pyridylmethoxy)phenoxy]-4-(2-methylphenyl)b utanoi c acid (12m). This compound exhibits low-nanomolar binding to the ETA receptor and a greater than 1000-fold selectivity over the ETB receptor. Data are presented to demonstrate that 12m is orally bioavailable in the rat and is a functional antagonist in vitro and in vivo of ET-1-induced vasoconstriction.
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