Potential Cancer Therapeutic Strategy Research Articles

Arginase-induced cell death pathways and metabolic changes in cancer cells are not altered by insulin

Arginine, a semi-essential amino acid, is critical for cell growth. Typically, de novo synthesis of arginine is sufficient to support cellular processes, however, it becomes vital for cancer cells that are unable to synthesise arginine due to enzyme deficiencies. Targeting this need, arginine depletion with enzymes such as arginase (ARG) has emerged as a potential cancer therapeutic strategy. Studies have proposed using high dose insulin to induce a state of hypoaminoacidaemia in the body, thereby further reducing circulating arginine levels. However, the mitogenic and metabolic properties of insulin could potentially counteract the therapeutic effects of ARG. Our study examined the combined impact of insulin and ARG on breast, lung, and ovarian cell lines, focusing on cell proliferation, metabolism, apoptosis, and autophagy. Our results showed that the influence of insulin on ARG uptake varied between cell lines but failed to promote the proliferation of ARG-treated cells or aid recovery post-ARG treatment. Moreover, insulin was largely ineffective in altering ARG-induced metabolic changes and did not prevent apoptosis. In vitro, at least, these findings imply that insulin does not offer a growth or survival benefit to cancer cells being treated with ARG.

Induction of autophagy-dependent and caspase- and microtubule-acetylation-independent cell death by phytochemical-stabilized gold nanopolygons in colorectal adenocarcinoma cells.

Collective functionalization of the phytochemicals of medicinal herbs on nanoparticles is emerging as a potential cancer therapeutic strategy. This study presents the facile synthesis of surface-functionalized gold nanoparticles using Bacopa monnieri (Brahmi; Bm) phytochemicals and their therapeutically relevant mechanism of action in the colorectal cancer cell line, HT29. The nanoparticles were characterized using UV-visible spectroscopy, TEM-EDAX, zeta potential analysis, TGA, FTIR and 1H NMR spectroscopy, and HR-LC-MS. The particles (Bm-GNPs) were of polygonal shape and were stable against aggregation. They entered the target cells and inhibited the viability and clonogenicity of the cells with eight times more antiproliferative efficacy (25 ± 1.5 μg mL-1) than Bm extract (Bm-EX). In vitro studies revealed that Bm-GNPs bind tubulin (a protein crucial in cell division and a target of anticancer drugs) and disrupt its helical structure without grossly altering its tertiary conformation. Like other antitubulin agents, Bm-GNPs induced G2/M arrest and ultimately killed the cells, as confirmed using flow cytometry analyses. ZVAD-FMK-mediated global pan-caspase inhibition and the apparent absence of cleaved caspase-3 in treated cells indicated that the death did not involve the classic apoptosis pathway. Cellular ultrastructure analyses, western immunoblots, and in situ immunofluorescence visualization of cellular microtubules revealed microtubule-acetylation-independent induction of autophagy as the facilitator of cell death. Together, the data indicate strong antiproliferative efficacy and a possible mechanism of action for these designer nanoparticles. Bm-GNPs, therefore, merit further investigations, including preclinical evaluations, for their therapeutic potential as inducers of non-apoptotic cell death.

Integrated multi-omics analysis reveals the molecular interplay between circadian clocks and cancer pathogenesis

Circadian rhythms (CRs) are fundamental biological processes that significantly impact human well-being. Disruption of these rhythms can trigger insufficient neurocognitive development, insomnia, mental disorders, cardiovascular diseases, metabolic dysfunctions, and cancer. The field of chronobiology has increased our understanding of how rhythm disturbances contribute to cancer pathogenesis, and how circadian timing influences the efficacy of cancer treatments. As the circadian clock steadily gains recognition as an emerging factor in tumorigenesis, a thorough and comprehensive multi-omics analysis of CR genes/proteins has never been performed. To shed light on this, we performed, for the first time, an integrated data analysis encompassing genomic/transcriptomic alterations across 32 cancer types (n = 10,918 tumors) taken from the PanCancer Atlas, unfavorable prognostic protein analysis, protein–protein interactomics, and shortest distance score pathways to cancer hallmark phenotypes. This data mining strategy allowed us to unravel 31 essential CR-related proteins involved in the signaling crossroad between circadian rhythms and cancer. In the context of drugging the clock, we identified pharmacogenomic clinical annotations and drugs currently in late phase clinical trials that could be considered as potential cancer therapeutic strategies. These findings highlight the diverse roles of CR-related genes/proteins in the realm of cancer research and therapy.

Metabolic reprogramming and epigenetic modifications in cancer: from the impacts and mechanisms to the treatment potential.

Metabolic reprogramming and epigenetic modifications are hallmarks of cancer cells. In cancer cells, metabolic pathway activity varies during tumorigenesis and cancer progression, indicating regulated metabolic plasticity. Metabolic changes are often closely related to epigenetic changes, such as alterations in the expression or activity of epigenetically modified enzymes, which may exert a direct or an indirect influence on cellular metabolism. Therefore, exploring the mechanisms underlying epigenetic modifications regulating the reprogramming of tumor cell metabolism is important for further understanding tumor pathogenesis. Here, we mainly focus on the latest studies on epigenetic modifications related to cancer cell metabolism regulations, including changes in glucose, lipid and amino acid metabolism in the cancer context, and then emphasize the mechanisms related to tumor cell epigenetic modifications. Specifically, we discuss the role played by DNA methylation, chromatin remodeling, noncoding RNAs and histone lactylation in tumor growth and progression. Finally, we summarize the prospects of potential cancer therapeutic strategies based on metabolic reprogramming and epigenetic changes in tumor cells.

Abstract 5511: Investigating Wee1 and Myt1 combined inhibition as a potential cancer therapeutic strategy

Abstract Introduction: Cell cycle is under the surveillance of checkpoints to repair any damage before the cell transits between phases. Wee1 and Myt1 kinases prevent premature entry into mitosis by monitoring the G2/M checkpoint by adding an inhibitory phosphorylation on Cdk1. Wee1 is overexpressed in various tumors and MK-1775, a Wee1 small molecule inhibitor, is currently in phase I/II cancer clinical trials. Although MK-1775 was shown to potentiate the effect of other genotoxic therapies, yet clinical resistance has emerged towards it. In examining the mechanism of MK-1775-mediated cytotoxicity, we identified Myt1 as a resistant factor. Emerging evidence suggests that Myt1 is an important cancer therapeutic target. Hence, we are examining a novel Myt1 kinase small molecule inhibitor, RP-6306 in combination with MK-1775 as a potential synthetic lethal cancer therapy. We hypothesize that a combination of MK-1775 and RP-6306, inhibitors against two partially redundant kinases important for adaptation to genotoxic stress, will achieve synthetic lethality while circumventing the issue of resistance development following monotherapies. Model Systems Used: 1) a cervical cancer cell line that is tetracycline inducible for Myt1 expression; 2) cancer cell lines (breast and cervical) that are resistant to MK-1775 through upregulation of Myt1. Methods: We established the IC50 of RP-6306 in a panel of tumorigenic and non-tumorigenic cell lines using standard crystal violet viability assay. Following that, we tested the combination effect of MK-1775 and RP-6306 in model cell lines listed above using zero potency model of synergy. The effect of the combination treatment on the clonogenicity was evaluated using clonogenic assay. Timelapse microscopy on a High Content Imaging system was used to determine the effect of RP-6306 and MK-1775 on mitotic duration and cell fates. Results: We found that MK-1775 and RP-6306 combination treatment shows synergistic cell killing in a panel of cancer cell lines. Wee1 inhibition shows synergistic cell killing with Myt1 inhibition especially in inducible Myt1 overexpressing cells. Wee1 and Myt1 combined inhibition resists the increase in clonogenic potential of the cancer cells transiently overexpressing Myt1. RP-6306 and MK-1775 combination treatment promotes mitotic arrest leading to cell death in Myt1 overexpressing cells. We also found that the mechanism of cell death in the cells treated with the combination treatment is centromere fragmentation leading to mitotic catastrophe. Conclusions: The combined Wee1 and Myt1 inhibition leads to synthetic lethality. Hence, our findings strongly suggest that the combined MK-1775 and RP-6306 treatment has promising potential to mitigate MK-1775 resistance. Our research contributes to the development of novel potential combination therapy while optimizing and improving the efficacy of MK-1775 treatment for potential clinical use. Citation Format: Sargun Sokhi, Joanne D. Hadfield, Jeremy Fung, Gordon K. Chan. Investigating Wee1 and Myt1 combined inhibition as a potential cancer therapeutic strategy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5511.

Generation and multiomic profiling of a TP53/CDKN2A double-knockout gastroesophageal junction organoid model.

Inactivation of the tumor suppressor genes tumor protein p53 (TP53) and cyclin-dependent kinase inhibitor 2A (CDKN2A) occurs early during gastroesophageal junction (GEJ) tumorigenesis. However, because of a paucity of GEJ-specific disease models, cancer-promoting consequences of TP53 and CDKN2A inactivation at the GEJ have not been characterized. Here, we report the development of a wild-type primary human GEJ organoid model and a CRISPR-edited transformed GEJ organoid model. CRISPR-Cas9-mediated TP53 and CDKN2A knockout (TP53/CDKN2AKO) in GEJ organoids induced morphologic dysplasia and proneoplastic features in vitro and tumor formation in vivo. Lipidomic profiling identified several platelet-activating factors (PTAFs) among the most up-regulated lipids in CRISPR-edited organoids. PTAF/PTAF receptor (PTAFR) abrogation by siRNA knockdown or a pharmacologic inhibitor (WEB2086) reduced proliferation and other proneoplastic features of TP53/CDKN2AKO GEJ organoids in vitro and tumor formation in vivo. In addition, murine xenografts of Eso26, an established human esophageal adenocarcinoma cell line, were suppressed by WEB2086. Mechanistically, TP53/CDKN2A dual inactivation disrupted both the transcriptome and the DNA methylome, likely mediated by key transcription factors, particularly forkhead box M1 (FOXM1). FOXM1 activated PTAFR transcription by binding to the PTAFR promoter, further amplifying the PTAF-PTAFR pathway. Together, these studies established a robust model system for investigating early GEJ neoplastic events, identified crucial metabolic and epigenomic changes occurring during GEJ model tumorigenesis, and revealed a potential cancer therapeutic strategy. This work provides insights into proneoplastic mechanisms associated with TP53/CDKN2A inactivation in early GEJ neoplasia, which may facilitate early diagnosis and prevention of GEJ neoplasms.

Targeting Extracellular Signal-Regulated Protein Kinase 1/2 (ERK1/2) in Cancer: An Update on Pharmacological Small-Molecule Inhibitors.

Extracellular signal-regulated protein kinase 1/2 (ERK1/2), the only known substrate of MEK1/2, is located downstream of the RAS-RAF-MEK-ERK (MAPK) pathway and is associated with the abnormal activation and poor prognosis of cancer. To date, several small-molecule inhibitors of RAS, RAF, and MEK have been reported to make rapid advances in cancer therapy; however, acquired resistance still occurs, thereby weakening the therapeutic efficacy of these inhibitors. Recently, selective inhibition of ERK1/2 has been regarded as a potential cancer therapeutic strategy that can not only effectively block the MAPK pathway but also overcome drug resistance caused by upstream mutations in RAS, RAF, and MEK. Herein, we summarize the oncogenic roles, key signaling network, and the single- and dual-target inhibitors of ERK1/2 in preclinical and clinical trials. Together, these inspiring findings shed new light on the discovery of more small-molecule inhibitors of ERK1/2 as candidate drugs to improve cancer therapeutics.

Ursolic acid-enriched kudingcha extract enhances the antitumor activity of bacteria-mediated cancer immunotherapy

BackgroundBacteria-mediated cancer immunotherapy (BCI) robustly stimulates the immune system and represses angiogenesis, but tumor recurrence and metastasis commonly occur after BCI. The natural product Ilex kudingcha C. J Tseng enriched with ursolic acid has anti-cancer activity and could potentially augment the therapeutic effects of BCI. The objective of the present study was to determine potential additive effects of these modalities.MethodsWe investigated the anti-cancer activity of KDCE (Kudingcha extract) combined with S.t△ppGpp in the mice colon cancer models.ResultsIn the present study, KDCE combined with S.t△ppGpp BCI improved antitumor therapeutic efficacy compared to S.t△ppGpp or KDCE alone. KDCE did not prolong bacterial tumor-colonizing time, but enhanced the antiangiogenic effect of S.t△ppGpp by downregulatingVEGFR2. We speculated that KDCE-induced VEGFR2 downregulation is associated with FAK/MMP9/STAT3 axis but not AKT or ERK.ConclusionsUrsolic acid-enriched KDCE enhances the antitumor activity of BCI, which could be mediated by VEGFR2 downregulation and subsequent suppression of angiogenesis. Therefore, combination therapy with S.t△ppGpp and KDCE is a potential cancer therapeutic strategy.

MAGCN: A Multiple Attention Graph Convolution Networks for Predicting Synthetic Lethality.

Synthetic lethality (SL) is a potential cancer therapeutic strategy and drug discovery. Computational approaches to identify synthetic lethality genes have become an effective complement to wet experiments which are time consuming and costly. Graph convolutional networks (GCN) has been utilized to such prediction task as be good at capturing the neighborhood dependency in a graph. However, it is still a lack of the mechanism of aggregating the complementary neighboring information from various heterogeneous graphs. Here, we propose the Multiple Attention Graph Convolution Networks for predicting synthetic lethality (MAGCN). First, we obtain the functional similarity features and topological structure features of genes from different data sources respectively, such as Gene Ontology data and Protein-Protein Interaction. Then, graph convolutional network is utilized to accumulate the knowledge from neighbor nodes according to synthetic lethal associations. Meanwhile, we propose a multiple graphs attention model and construct a multiple graphs attention network to learn the contribution factors of different graphs to generate embedded representation by aggregating these graphs. Finally, the generated feature matrix is decoded to predict potential synthetic lethal interaction. Experimental results show that MAGCN is superior to other baseline methods. Case study demonstrates the ability of MAGCN to predict human SL gene pairs.

Green Synthesis of Gold Nanoparticles Using Plant Extracts as Beneficial Prospect for Cancer Theranostics.

Gold nanoparticles (AuNPs) have been widely explored and are well-known for their medical applications. Chemical and physical synthesis methods are a way to make AuNPs. In any case, the hunt for other more ecologically friendly and cost-effective large-scale technologies, such as environmentally friendly biological processes known as green synthesis, has been gaining interest by worldwide researchers. The international focus on green nanotechnology research has resulted in various nanomaterials being used in environmentally and physiologically acceptable applications. Several advantages over conventional physical and chemical synthesis (simple, one-step approach to synthesize, cost-effectiveness, energy efficiency, and biocompatibility) have drawn scientists’ attention to exploring the green synthesis of AuNPs by exploiting plants’ secondary metabolites. Biogenic approaches, mainly the plant-based synthesis of metal nanoparticles, have been chosen as the ideal strategy due to their environmental and in vivo safety, as well as their ease of synthesis. In this review, we reviewed the use of green synthesized AuNPs in the treatment of cancer by utilizing phytochemicals found in plant extracts. This article reviews plant-based methods for producing AuNPs, characterization methods of synthesized AuNPs, and discusses their physiochemical properties. This study also discusses recent breakthroughs and achievements in using green synthesized AuNPs in cancer treatment and different mechanisms of action, such as reactive oxygen species (ROS), mediated mitochondrial dysfunction and caspase activation, leading to apoptosis, etc., for their anticancer and cytotoxic effects. Understanding the mechanisms underlying AuNPs therapeutic efficacy will aid in developing personalized medicines and treatments for cancer as a potential cancer therapeutic strategy.

Evaluation of the Cytotoxic Effects of the Novel Antineoplastic Agent 1,4,5-Oxathiazinane-4,4-dioxide on Triple Negative Breast Cancer Cells.

Adjuvant therapeutic options are limited for triple negative breast cancer (TNBC). Thus, we evaluated the cytotoxic effects of the newly synthesized antineoplastic agent 1,4,5-Oxathiazinane-4,4-dioxide (OTD) on TNBC cells as a potential cancer therapeutic strategy. TNBC primary BT-20 and metastatic MDA-MB-231 cell lines were treated with increasing concentrations of OTD for various time periods to assess cell viability. Cell necrosis, apoptosis, necroptosis, autophagy, and ROS generation were evaluated using assay kits or specific inhibitors. Treatment with OTD resulted in a dose- and time-dependent cell death of TNBC BT-20 and MDA-MB-231 cells. OTD also dose-dependently arrested TNBC cell proliferation. Notably, treatment with OTD induced both necrosis and apoptosis of TNBC cells, while the pan-caspase inhibitor Z-VAD-FMK partially attenuated OTD-induced cell death. Importantly, abrogated OTD-induced cell death was observed in the presence of the ROS scavenger N-acetylcysteine (NAC), whereas enhanced OTD-induced cell death was observed after the addition of the glutathione synthesis inhibitor BSO, indicating OTD-induced killing of TNBC cells via a reactive oxygen species-dependent mechanism. OTD is strongly cytotoxic to both primary and metastatic TNBC cells, possibly by inducing multiple cell death pathways.

Protein disulphide isomerase inhibition as a potential cancer therapeutic strategy.

The protein disulphide isomerase (PDI) gene family is a large, diverse group of enzymes recognised for their roles in disulphide bond formation within the endoplasmic reticulum (ER). PDI therefore plays an important role in ER proteostasis, however, it also shows involvement in ER stress, a characteristic recognised in multiple disease states, including cancer. While the exact mechanisms by which PDI contributes to tumorigenesis are still not fully understood, PDI exhibits clear involvement in the unfolded protein response (UPR) pathway. The UPR acts to alleviate ER stress through the activation of ER chaperones, such as PDI, which act to refold misfolded proteins, promoting cell survival. PDI also acts as an upstream regulator of the UPR pathway, through redox regulation of UPR stress receptors. This demonstrates the pro‐protective roles of PDI and highlights PDI as a potential therapeutic target for cancer treatment. Recent research has explored the use of PDI inhibitors with PACMA 31 in particular, demonstrating promising anti‐cancer effects in ovarian cancer. This review discusses the properties and functions of PDI family members and focuses on their potential as a therapeutic target for cancer treatment.

Intracellular Ca2 + Imbalance Critically Contributes to Paraptosis.

Paraptosis is a type of programmed cell death that is characterized by dilation of the endoplasmic reticulum (ER) and/or mitochondria. Since paraptosis is morphologically and biochemically different from apoptosis, understanding its regulatory mechanisms may provide a novel therapeutic strategy in malignant cancer cells that have proven resistant to conventional pro-apoptotic treatments. Relatively little is known about the molecular basis of paraptosis, but perturbations of cellular proteostasis and ion homeostasis appear to critically contribute to the process. Ca2+ transport has been shown to be important in the paraptosis induced by several natural products, metal complexes, and co-treatment with proteasome inhibitors and certain Ca2+-modulating agents. In particular, the Ca2+-mediated communication between the ER and mitochondria plays a crucial role in paraptosis. Mitochondrial Ca2+ overload from the intracellular Ca2+-flux system located at the ER–mitochondrial axis can induce mitochondrial dilation during paraptosis, while the accumulation of misfolded proteins within the ER lumen is believed to exert an osmotic force and draw water from the cytoplasm to distend the ER lumen. In this process, Ca2+ release from the ER also critically contributes to aggravating ER stress and ER dilation. This review focuses on the role of Ca2+ transport in paraptosis by summarizing the recent findings related to the actions of Ca2+-modulating paraptosis-inducing agents and discussing the potential cancer therapeutic strategies that may effectively induce paraptosis via Ca2+ signaling.

Adaptive response of resistant cancer cells to chemotherapy.

Despite advances in cancer therapeutics and the integration of personalized medicine, the development of chemoresistance in many patients remains a significant contributing factor to cancer mortality. Upon treatment with chemotherapeutics, the disruption of homeostasis in cancer cells triggers the adaptive response which has emerged as a key resistance mechanism. In this review, we summarize the mechanistic studies investigating the three major components of the adaptive response, autophagy, endoplasmic reticulum (ER) stress signaling, and senescence, in response to cancer chemotherapy. We will discuss the development of potential cancer therapeutic strategies in the context of these adaptive resistance mechanisms, with the goal of stimulating research that may facilitate the development of effective cancer therapy.

Role of the RAB7 Protein in Tumor Progression and Cisplatin Chemoresistance.

RAB7 is a small guanosine triphosphatase (GTPase) extensively studied as regulator of vesicular trafficking. Indeed, its role is fundamental in several steps of the late endocytic pathway, including endosome maturation, transport from early endosomes to late endosomes and lysosomes, clustering and fusion of late endosomes and lysosomes in the perinuclear region and lysosomal biogenesis. Besides endocytosis, RAB7 is important for a number of other cellular processes among which, autophagy, apoptosis, signaling, and cell migration. Given the importance of RAB7 in these cellular processes, the interest to study the role of RAB7 in cancer progression is widely grown. Here, we describe the current understanding of oncogenic and oncosuppressor functions of RAB7 analyzing cellular context and other environmental factors in which it elicits pro and/or antitumorigenic effects. We also discuss the role of RAB7 in cisplatin resistance associated with its ability to regulate the late endosomal pathway, lysosomal biogenesis and extracellular vesicle secretion. Finally, we examined the potential cancer therapeutic strategies targeting the different molecular events in which RAB7 is involved.

Targeting the Central Pocket in Human Transcription Factor TEAD as a Potential Cancer Therapeutic Strategy

The human TEAD family of transcription factors (TEAD1-4) is required for YAP-mediated transcription in the Hippo pathway. Hyperactivation of TEAD's co-activator YAP contributes to tissue overgrowth and human cancers, suggesting that pharmacological interference of TEAD-YAP activity may be an effective strategy for anticancer therapy. Here we report the discovery of a central pocket in the YAP-binding domain (YBD) of TEAD that is targetable by small-molecule inhibitors. Our X-ray crystallography studies reveal that flufenamic acid, a non-steroidal anti-inflammatory drug (NSAID), binds to the central pocket of TEAD2 YBD. Our biochemical and functional analyses further demonstrate that binding of NSAIDs to TEAD inhibits TEAD-YAP-dependent transcription, cell migration, and proliferation, indicating that the central pocket is important for TEAD function. Therefore, our studies discover a novel way of targeting TEAD transcription factors and set the stage for therapeutic development of specific TEAD-YAP inhibitors against human cancers.

The Regulation and Interactions of the Hypoxia Inducible Factor Pathway in Carcinogenesis and Potential Cancer Therapeutic Strategies

The Hypoxia Inducible factor (HIF) pathway is known to be constitutionally active in various cancers and is the dominant pathway in some cancers such as VHL mutant clear cell Renal cell carcinoma. HIF-1α and HIF-2α overexpression is known to be important for tumor cell proliferation, maintenance of stemness and angiogenesis. There has been growing interest in therapeutic strategies targeting the HIF pathway over the last decade. We review in this section the role of hypoxia inducible factor pathway in carcinogenesis, its crosstalk with other pathways and potential cancer therapeutic strategies targeting the HIF pathway, its upstream regulators and downstream signaling.

Ursolic acid promotes cancer cell death by inducing Atg5‐dependent autophagy

Ursolic acid (UA) has been reported to possess anticancer activities. Although some of the anticancer activities of UA have been explained by its apoptosis-inducing properties, the mechanisms underlying its anticancer actions are largely unknown. We have found that UA-activated autophagy induced cytotoxicity and reduced tumor growth of cervical cancer cells TC-1 in a concentration-dependent manner. UA did not induce apoptosis of TC-1 cells in vitro as determined by annexin V/propidium iodide staining, DNA fragmentation, and Western blot analysis of the apoptosis-related proteins. We found that UA increased punctate staining of light chain 3 (LC3), which is an autophagy marker. LC3II, the processed form of LC3I which is formed during the formation of double membranes, was induced by UA treatment. These results were further confirmed by transmission electron microscopy. Wortmannin, an inhibitor of autophagy, and a small interfering RNA (siRNA) for autophagy-related genes (Atg5) reduced LC3II and simultaneously increased the survival of TC-1 cells treated with UA. We also found that LC3II was significantly reduced and that survival was increased in Atg5-/- mouse embryonic fibroblast (MEF) cells compared to Atg5+/+ MEF cells under UA treatment. However, silencing BECN1 by siRNA affected neither the expression of LC3II nor the survival of TC-1 cells under UA treatment. These results suggest that autophagy is a major mechanism by which UA kills TC-1 cells. It is Atg5 rather than BECN1 that plays a crucial role in UA-induced autophagic cell death in TC-1 cells. The activation of autophagy by UA may become a potential cancer therapeutic strategy complementing the apoptosis-based therapies. Furthermore, regulation of Atg5 may improve the efficacy of UA in cancer treatment.

Bcl-2 turns deadly

Small-molecule inhibitors of anti-apoptotic Bcl-2 proteins and BH3 mimetic peptides are promising anticancer agents. A recent study identifies a Nur77-based peptide that converts anti-apoptotic Bcl-2 proteins into proapoptotic molecules, providing another potential cancer therapeutic strategy.

X ray responses of a human colon tumor cell line after exposure to the differentiation-inducing agent N-methylformamide: Concentration dependence and reversibility characteristics

The combination of differentiation-inducing agents with conventional cytotoxic agents has been suggested as a potential cancer therapeutic strategy. In this regard, we have chronically exposed (3 passages) a human colon tumor line (clone A) to varying concentrations (0–170 mM) of N-methylformamide and examined the change in sensitivity to ionizing radiation in vitro. The linear-quadratic formalism of survival was used to characterize the single graded dose survival curves. This equation yields two constants (α and β) relating to cellular inactivation produced by either single events (α) or by the combination of two events (β). As the N-methylformamide concentration increased, the a parameter increased while the β parameter concomitantly decreased, yielding a concentration dependent radiosensitization which was most marked in the low dose region of the survival curve. Upon removal of NMF, the original radiation resistance was regained within 2–3 cell culture doubling times.