gx-15-070 and Neoplasms

Topics: Aniline Compounds; Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Apoptosis Regulatory Proteins; Bridged Bicyclo Compounds, Heterocyclic; Drug Screening Assays, Antitumor; Humans; Indoles; MAP Kinase Signaling System; Mitochondrial Dynamics; Molecular Targeted Therapy; Neoplasm Proteins; Neoplasms; Oncogene Addiction; Proto-Oncogene Proteins c-bcl-2; Pyrroles; Sulfonamides

Autophagy is an essential catabolic program that forms part of the stress response and enables cells to break down their own intracellular components within lysosomes for recycling. Accumulating evidence suggests that autophagy plays vital roles in determining pathological outcomes of immune responses and tumorigenesis. Autophagy regulates innate and adaptive immunity affecting the pathologies of infectious, inflammatory, and autoimmune diseases. In cancer, autophagy appears to play distinct roles depending on the context of the malignancy by either promoting or suppressing key determinants of cancer cell survival. This review covers recent developments in the understanding of autophagy and discusses potential therapeutic interventions that may alter the outcomes of certain diseases.

Topics: Adaptive Immunity; Animals; Autoimmune Diseases; Autophagy; Benzylisoquinolines; Cholecalciferol; Humans; Immune System Diseases; Immunity, Innate; Indoles; Infections; Isoquinolines; Lysosomes; Maprotiline; Metformin; Neoplasms; Phenols; Pyrroles; Resveratrol; Sirolimus; Spermidine; Stilbenes; Tetrahydroisoquinolines; Trehalose

Targeting apoptosis is an attractive approach in cancer therapy. The BH3-only proteins of the BCL-2 family (having only the BCL-2 homology domain BH3) can trigger apoptosis by binding to the prosurvival members of this family and neutralizing their functional activity (sequestration of the proapoptotic Bcl-2 family members). The "BH3 mimetic" concept has prompted the development of small molecules capable of mimicking BH3-only proteins and thus inducing apoptosis. The prototype BH3 mimetic ABT-737 selectively targets the three prosurvival proteins BCL-XL, BCL-2, and BCL-W (but not MCL-1 or A1) and its oral derivative ABT-263 has proved promising in clinical trials. Some putative BH3 mimetics are also tested clinically while others are still being characterized. This article recapitulates the various known BH3 mimetics and presents the recent developments in the field. The latter include (i) the identification of molecular determinants responsible for the specific interactions between BH3 motifs and the binding grooves of prosurvival proteins and (ii) the characterization of new compounds and particularly BH3 mimetics that antagonize either selectively MCL-1 or BCL-2 or a broad range of prosurvival proteins. These data are critical advances toward the discovery of novel anticancer agents.

Topics: Amino Acid Motifs; Aniline Compounds; Antineoplastic Agents; Apoptosis; Bridged Bicyclo Compounds, Heterocyclic; Clinical Trials as Topic; Drug Design; Drug Screening Assays, Antitumor; Gossypol; Humans; Indoles; Molecular Mimicry; Neoplasms; Peptide Fragments; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Pyrroles; Sulfonamides

Dose-limiting toxicity to healthy tissues is among the major hurdles in anticancer treatment along with intrinsic or acquired multi-drug resistance. Development of small molecule inhibitors (SMI) specific for antiapoptotic Bcl-2 proteins is a novel approach in a way that these antagonists are aimed to interfere with specific protein-protein interactions unlike conventional chemo-/radiotherapies. SMIs of antiapoptotic Bcl-2 proteins are assumed to compete with proapoptotic Bcl-2s to occupy BH3 docking grooves on the surfaces of antiapoptotic family members. Instead of directly initiating cell death, these inhibitors are intended to decrease apoptotic threshold in tumor cells that were already primed to death. In this regard, antiapoptotic Bcl-2 protein SMIs have the advantage of lower normal tissue toxicity relative to conventional anticancer therapies that interfere with general mechanisms including DNA synthesis, mitosis and tyrosine kinase activity. Besides, Bcl-2 antagonists were shown to potentiate efficacies of established drugs in several hematological malignancies and solid tumors which render them promising candidates for combination anticancer therapy. Utilizing these SMIs in such a way may prove to decrease the patient drug load by diminishing the required chemo-/radiotherapy dose. This review summarizes and compares BH3 mimetics on the basis of specificity, mode of action and efficacy, as well as providing remarks on their therapeutical potential and routes of development in near future.

Topics: Antineoplastic Agents; Apoptosis; Clinical Trials as Topic; Gossypol; Humans; Indoles; Models, Biological; Molecular Mimicry; Neoplasms; Proto-Oncogene Proteins c-bcl-2; Pyrroles

The B-cell lymphoma/leukemia 2 (BCL-2) family of proteins has attracted the attention of cancer biologists since the cloning of BCL-2 more than 25 years ago. In the intervening decades, the way the BCL-2 family controls commitment to programmed cell death has been greatly elucidated. Several drugs directed at inhibiting BCL-2 and related antiapoptotic proteins have been tested clinically, with some showing considerable promise, particularly in lymphoid malignancies. A better understanding of the BCL-2 family has also provided insight into how conventional chemotherapy selectively kills cancer cells and why some cancers are more chemosensitive than others. Further exploitation of our understanding of the BCL-2 family promises to offer improved predictive biomarkers for oncologists and improved therapies for patients with cancer.

Topics: Aniline Compounds; Animals; Antineoplastic Agents; Apoptosis; Biphenyl Compounds; Drug Resistance, Neoplasm; Humans; Indoles; Molecular Targeted Therapy; Neoplasms; Nitrophenols; Piperazines; Proto-Oncogene Proteins c-bcl-2; Pyrroles; Sulfonamides; Thionucleotides; Treatment Outcome

Apoptosis is involved in the action of several (and perhaps all) cancer-chemotherapeutic agents. Prodiginines are a family of natural red pigmented secondary metabolites, produced by different bacteria and most of them are characterized by a common pyrrolylpyrromethene skeleton. The biosynthesis of prodigiosin and derivatives has been extensively studied in Serratia marcescens. S. marcescens is a Gramnegative bacterium belonging to Enterobacteriaceae. Prodiginines show numerous biological activities pointing out immunosuppressive and anticancer properties. Some prodiginines displayed apoptotic effects in vitro and antitumor activity in vivo. Their cytotoxic effect is attributed to the presence of the C- 6 methoxy substituent. The A-pyrrole ring plays a key role in both the copper nuclease activity and the cytotoxicity of prodiginines. Here we review the main characteristics of prodigiosin and their derivatives as well as the most prominent pharmacological activity of prodiginines and related compounds, including novel synthetic PG-derivatives with lower toxicity like GX15-070 (Obatoclax). The molecular targets of prodiginines are discussed and the mechanism of action for these molecules is a current topic in biomedicine with a real therapeutica potential in the clinic.

Topics: Antineoplastic Agents; Apoptosis; Cell Cycle; DNA Damage; Humans; Indoles; Neoplasms; Prodigiosin; Pyrroles; Serratia; Signal Transduction

Inhibiting apoptosis is widely accepted as a necessary step in the transition from normal to cancer cells, and most cancer therapies exert their effects by indirectly reversing this process. Commitment to apoptosis is caused by permeabilisation of the outer mitochondrial membrane--a process regulated by the binding between different members of the Bcl-2 family. Furthermore, Bcl-2 family members also bind to the endoplasmic reticulum, where they modify processes such as the unfolded-protein response and autophagy that also cause or modify different types of cell death. With the growing understanding of the importance of the Bcl-2 family as crucial regulators of the decision to initiate apoptosis, much effort has been directed at developing small molecules that modify function by directly binding to Bcl-2 proteins. Preclinical experiments have confirmed that these agents kill cancer cells and overcome chemotherapy resistance. Two of these drugs are in the initial stages of clinical development (ABT-263 and obatoclax), and early results show clinical efficacy at tolerable doses. Important questions for the future include the role of these drugs as monotherapy versus combination therapy with other anticancer drugs, and the related issue of the relative toxicity to cancerous versus normal cells.

Topics: Aniline Compounds; Antineoplastic Agents; Drug Delivery Systems; Humans; Indoles; Neoplasms; Protein Binding; Proto-Oncogene Proteins c-bcl-2; Pyrroles; Sulfonamides

A critical regulator of the apoptotic machinery is the Bcl-2 family proteins whose over expression confers a protective effect on malignant cells against death signals of apoptosis. Cancer cells that are resistant to various anti-cancer drugs and treatment regimen are found to over express these Bcl-2 proteins such as Bcl-2, Bcl-X(L), Mcl-1, Bcl-w, and A1/Bfl1. In recent years there has been an exponential growth in the identification as well as synthesis of non-peptidic cell permeable small-molecule inhibitors (SMIs) of protein-protein interaction. The focus of this article is on inhibitors of anti-apoptotic protein Bcl-2. This review summarizes an up to date knowledge of the available SMIs, their mode of action as well as their current status in preclinical as well as clinical development.

Topics: Aniline Compounds; Animals; Apoptosis; Benzamides; Binding Sites; Biphenyl Compounds; Gossypol; Humans; Indoles; Lymphoma; Models, Molecular; Neoplasms; Nitrophenols; Piperazines; Protein Structure, Tertiary; Proto-Oncogene Proteins c-bcl-2; Pyrroles; Sulfonamides; Sulfones

Defects in apoptotic pathways can promote cancer cell survival and also confer resistance to antineoplastic drugs. One pathway being targeted for antineoplastic therapy is the anti-apoptotic B-cell lymphoma-2 (Bcl-2) family of proteins (Bcl-2, Bcl-XL, Bcl-w, Mcl-1, Bfl1/A-1, and Bcl-B) that bind to and inactivate BH3-domain pro-apoptotic proteins. Signals transmitted by cellular damage (including antineoplastic drugs) or cytokine deprivation can initiate apoptosis via the intrinsic apoptotic pathway. It is controversial whether some BH3-domain proteins (Bim or tBid) directly activate multidomain pro-apoptotic proteins (e.g., Bax and Bak) or act via inhibition of those anti-apoptotic Bcl-2 proteins (Bcl-2, Bcl-XL, Bcl-w, Mcl-1, Bfl1/A-1, and Bcl-B) that stabilize pro-apoptotic proteins. Overexpression of anti-apoptotic Bcl-2 family members has been associated with chemotherapy resistance in various human cancers, and preclinical studies have shown that agents targeting anti-apoptotic Bcl-2 family members have preclinical activity as single agents and in combination with other antineoplastic agents. Clinical trials of several investigational drugs targeting the Bcl-2 family (oblimersen sodium, AT-101, ABT-263, GX15-070) are ongoing. Here, we review the role of the Bcl-2 family in apoptotic pathways and those agents that are known and/or designed to inhibit the anti-apoptotic Bcl-2 family of proteins.

Topics: Aniline Compounds; Animals; Antineoplastic Agents; Apoptosis; Biphenyl Compounds; Gossypol; Humans; Indoles; Mitochondria; Neoplasms; Nitrophenols; Piperazines; Proto-Oncogene Proteins c-bcl-2; Pyrroles; Sulfonamides; Thionucleotides

Cancer cells show deviant behavior that induces apoptotic signaling. To survive, cancer cells typically acquire changes enabling evasion of death signals. One way they do this is by increasing the expression of anti-apoptotic BCL-2 proteins. Anti-apoptotic BCL-2 family proteins antagonize death signaling by forming heterodimers with pro-death proteins. Heterodimer formation occurs through binding of the pro-apoptotic protein's BH3 domain into the hydrophobic cleft of anti-apoptotic proteins. The BH3 mimetics are small molecule antagonists of the anti-apoptotic BCL-2 members that function as competitive inhibitors by binding to the hydrophobic cleft. Under certain conditions, antagonism of anti-apoptotic BCL-2 family proteins can unleash pro-death molecules in cancer cells. Thus, the BH3 mimetics are a new class of cancer drugs that specifically target a mechanism of cancer cell survival to selectively kill cancer cells.

Topics: Aniline Compounds; Animals; Antineoplastic Agents; Apoptosis; Benzamides; Binding, Competitive; Biphenyl Compounds; Clinical Trials as Topic; Dimerization; Drug Delivery Systems; Drug Design; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Humans; Indoles; Mice; Mitochondria; Multigene Family; Neoplasm Proteins; Neoplasms; Nitrophenols; Piperazines; Protein Structure, Tertiary; Proto-Oncogene Proteins c-bcl-2; Pyrroles; Structure-Activity Relationship; Sulfonamides; Sulfones; Thionucleotides

Two phase I, single-agent studies were conducted to determine the dose and regimen of obatoclax, an antagonist of all BCL-2 antiapoptotic proteins, for evaluation in phase II trials. The two studies, GX001 and GX005, evaluated the safety and tolerability of weekly 1-hour and 3-hour infusions of obatoclax, respectively.. Eligible patients in both studies were adults with solid tumor or lymphoma and performance status 0-1 for whom standard therapies were not appropriate. In the GX001 study an accelerated dose titration design was initially used with subsequent cohorts of three to six patients with 40% dose increments between levels. In the GX005 study three to six patients entered at each dose level with 40% dose increments between levels.. Thirty-five patients were enrolled in studies GX001 (n = 8) and GX005 (n = 27). Clinically significant central nervous system (CNS) toxicity was observed using the 1-hour infusion schedule. The obatoclax maximum tolerated dose (MTD) in GX001 was 1.25 mg/m(2) due to these infusional CNS events. The 3-hour infusion schedule studied in GX005 had improved tolerability, and the obatoclax MTD was 20 mg/m(2). One patient in GX005 with relapsed non-Hodgkin's lymphoma achieved partial response of 2 months' duration, and one patient with relapsed non-Hodgkin's lymphoma had stable disease for 18 months.. The 1-hour infusion schedule of obatoclax was associated with neuropsychiatric dose-limiting toxicities at relatively low doses (MTD, 1.25 mg/m(2)). The 3-hour i.v. infusion of obatoclax administered once weekly to patients with solid tumors was better tolerated (MTD, 20 mg/m(2)), and evidence of clinical activity was observed.

Topics: Adult; Aged; Antineoplastic Agents; Area Under Curve; Dose-Response Relationship, Drug; Female; Humans; Indoles; Lymphoma; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Proto-Oncogene Proteins c-bcl-2; Pyrroles; Remission Induction

By hindering energy supply pathway for cancer cells, an alternative therapeutic strategy modality is put forward: tumor starvation therapy. And yet only in this blockade of glucose supply which is far from enough to result in sheer apoptosis of cancer cells.. In an effort to boost nutrient starvation-dominated cancer therapy, here a novel mitochondrial Ca. Here, a promising complementary modality for the trebling additive efficacy of starvation therapy was described for cutting off the existing energy sources in starvation therapy through Curcumin-augmented mitochondrial Ca

Topics: Apoptosis; Autophagy; Cell Line, Tumor; Curcumin; Glucose; Humans; Indoles; Neoplasms; Nutrients; Pyrroles; Starvation

Three-dimensional (3D) culture systems such as floating spheroids (FSs) and floating tumorspheres (FTs) are widely used as tumor models of chemoresistance. FTs are considered to be enriched in cancer stem-like cells (CS-LCs). In this study, we used cancer cell lines (lung H460, prostate LnCAP, and breast MCF-7) able to form FSs under anchorage-independent conditions and compared with cell lines (prostate PC3 and breast MDA-MB-231) that cannot form FSs under similar conditions. Independent of their ability to form FTs all cell lines growing under anchorage-independent conditions become highly resistant to obatoclax, colchicine, and hydroxyurea. We used anti-E-cadherin antibody (that blocked the formation of FSs) and demonstrated that floating LnCAP cells showed similar chemoresistance regardless of the formation of spheroids. Our results demonstrate that the development of chemoresistance is not because of the formation of a complex 3D structure and/or enrichment of CS-LCs but is likely the result of cell detachment per se and their ability to survive under anchorage-independent conditions. We propose that FSs and FTs could be useful models to study chemoresistance of cancer cells associated with cell detachment (e.g., circulating tumor cells) but they may not be representative of other types of chemoresistance that arise in vivo in attached cells.

Topics: Antibodies; Antigens, CD; Antineoplastic Agents; Cadherins; Cell Adhesion; Cell Culture Techniques; Cell Survival; Colchicine; Culture Media, Serum-Free; Drug Resistance, Neoplasm; Female; Humans; Hydroxyurea; Indoles; Male; MCF-7 Cells; Neoplasms; PC-3 Cells; Phenotype; Pyrroles; Spheroids, Cellular

Prior studies in breast cancer cells have shown that lapatinib and obatoclax interact in a greater than additive fashion to cause cell death and do so through a toxic form of autophagy. The present studies sought to extend our analyses to the central nervous system (CNS) tumor cells and to further define mechanisms of drug action. Lapatinib and obatoclax killed multiple CNS tumor isolates. Cells lacking PTEN (phosphatase and tensin homolog on chromosome 10) function were relatively resistant to drug combination lethality; expression of PTEN in PTEN-null cells restored drug sensitivity, and knockdown of PTEN promoted drug resistance. On the basis of knockdown of ERBB1-4 (erythroblastic leukemia viral oncogene homolog 1-4), we discovered that the inhibition of ERBB1/3/4 receptors were most important for enhancing obatoclax lethality rather than ERBB2. In parallel, we noted in CNS tumor cells that knockdown of BCL-xL (B-cell lymphoma-extra large)and MCL-1 (myeloid cell leukemia-1) interacted in an additive fashion to facilitate lapatinib lethality. Pretreatment of tumor cells with obatoclax enhanced the lethality of lapatinib to a greater extent than concomitant treatment. Treatment of animals carrying orthotopic CNS tumor isolates with lapatinib- and obatoclax-prolonged survival. Altogether, our data show that lapatinib and obatoclax therapy could be of use in the treatment of tumors located in the CNS.

Topics: Antineoplastic Agents; Autophagy; bcl-X Protein; Cell Line, Tumor; ErbB Receptors; Humans; Indoles; Lapatinib; Myeloid Cell Leukemia Sequence 1 Protein; Neoplasms; Proto-Oncogene Proteins c-bcl-2; PTEN Phosphohydrolase; Pyrroles; Quinazolines; Receptor, ErbB-3; Receptor, ErbB-4

Resistance to cisplatin chemotherapy remains a major hurdle preventing effective treatment of many solid cancers. BAX and BAK are pivotal regulators of the mitochondrial apoptosis pathway, however little is known regarding their regulation in cisplatin resistant cells. Cisplatin induces DNA damage in both sensitive and resistant cells, however the latter exhibits a failure to initiate N-terminal exposure of mitochondrial BAK or mitochondrial SMAC release. Both phenotypes are highly sensitive to mitochondrial permeabilisation induced by exogenous BH3 domain peptides derived from BID, BIM, NOXA (which targets MCL-1 and A1), and there is no significant change in their prosurvival BCL2 protein expression profiles. Obatoclax, a small molecule inhibitor of pro-survival BCL-2 family proteins including MCL-1, decreases cell viability irrespective of platinum resistance status across a panel of cell lines selected for oxaliplatin resistance. In summary, selection for platinum resistance is associated with a block of mitochondrial death signalling upstream of BAX/BAK activation. Conservation of sensitivity to BH3 domain induced apoptosis can be exploited by agents such as obatoclax, which directly target the mitochondria and BCL-2 family.

Topics: Adenosine Triphosphate; Apoptosis; bcl-2 Homologous Antagonist-Killer Protein; bcl-2-Associated X Protein; Blotting, Western; Cell Line, Tumor; Cell Survival; Cisplatin; DNA Damage; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Humans; Indoles; Mitochondria; Neoplasms; Peptides; Platinum; Protein Structure, Tertiary; Protein Transport; Pyrroles

Escape from apoptosis is often a hallmark of cancer cells, and is associated to chemotherapy resistance or tumor relapse. Proteins from the Bcl-2 family are the key regulators of the intrinsic pathway of apoptosis, controlling the point-of no-return and setting the threshold to engage the death machinery in response to a chemical damage. Therefore, Bcl-2 proteins have emerged as an attractive target to develop novel anticancer drugs. Current pharmacological approaches are focused on the use of peptides, small inhibitory molecules or antisense oligonucleotides to neutralize antiapoptotic Bcl-2 proteins, lowering the threshold and facilitating apoptosis of cancer cells. We discuss here recent advances in the development of Bcl-2 targeted anticancer therapies.

Topics: Antineoplastic Agents; Apoptosis; Benzopyrans; BH3 Interacting Domain Death Agonist Protein; Biological Products; Genes, bcl-2; Gossypol; Humans; Indoles; Neoplasms; Nitriles; Oligonucleotides, Antisense; Proto-Oncogene Proteins c-bcl-2; Pyrroles

Topics: Antineoplastic Agents; Controlled Clinical Trials as Topic; Humans; Hydrazines; Indoles; Melanoma; Neoplasm Metastasis; Neoplasms; Pyrroles

Members of the BCL-2 family of proteins regulate and execute many cell intrinsic apoptosis pathways, including those arising from dysregulated expression of cellular oncogenes. Since pro-survival members of the family are often strongly elevated in diverse cancers, with the potential to confer resistance to both endogenous cell death stimuli and many cancer treatments, there has been intense interest to develop strategies to therapeutically modulate their activity. Although encouraging genetic and pharmacological preclinical proof of concept has been obtained, the challenge for clinical development will be to devise strategies that address the fact that multiple pro-survival members are typically up-regulated in a given cancer and the family operates primarily through protein-protein interactions. Moreover, since several current therapies themselves are known to stimulate the levels of one or more family members, there will be additional challenges (and opportunities) in exploiting this target in the clinic. In this review, we describe the rationale for targeting the BCL-2 family of apoptosis suppressors in cancer and the progress that has been made in modulating the family by small molecule antagonists.

Topics: Animals; Apoptosis; Biphenyl Compounds; Cell Line, Tumor; Cell Survival; Genes, myc; Humans; Indoles; Models, Animal; Neoplasms; Nitrophenols; Oncogenes; Piperazines; Proto-Oncogene Proteins c-bcl-2; Proto-Oncogene Proteins c-myc; Pyrroles; Sulfonamides