Role of Immune Cells and Immunotherapy in Multiple Myeloma.

The clinical signs of multiple myeloma, a plasma cell (PC) dyscrasia, include bone loss, renal damage, and paraproteinemia. It can be defined as the uncontrolled growth of malignant PCs within the bone marrow. The distinctive bone marrow milieu that regulates the progression of myeloma disease involves interactions between plasma and stromal cells, and myeloid and lymphoid cells. These cells affect the immune system independently or because of a complicated web of interconnections, which promotes disease development and immune evasion. Due to the importance of these factors in the onset of disease, various therapeutic strategies have been created that either target or improve the immunological processes that influence disease progression. The immune system has a role in the mechanism of action of multiple myeloma treatments. The main contributions of immune cells to the bone marrow microenvironment, as well as how they interact and how immune regulation might lead to therapeutic effects, are covered in this study.

Recent Advances towards the Understanding of Secondary Acute Myeloid Leukemia Progression.

Secondary acute myeloid leukemia (sAML) is a heterogeneous malignant hematopoietic disease that arises either from an antecedent hematologic disorder (AHD) including myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), aplastic anemia (AA), or as a result of exposure to genotoxic chemotherapeutic agents or radiotherapy (therapy related AML, tAML). sAML is diagnosed when the number of blasts is ≥20% in the bone marrow or peripheral blood, and it is characterized by poor prognosis, resistance to therapy and low overall survival rate. With the recent advances in next generation sequencing technologies, our understanding of the molecular events associated with sAML evolution has significantly increased and opened new perspectives for the development of novel therapies. The genetic aberrations that are associated with sAML affect genes involved in processes such as splicing, chromatin modification and genome integrity. Moreover, non-coding RNAs' emerged as an important contributing factor to leukemogenesis. For decades, the standard treatment for secondary AML has been the 7 + 3 regimen of cytarabine and daunorubicin which prolongs survival for several months, but modifications in either dosage or delivery has significantly extended that time. Apart from traditional chemotherapy, hematopoietic stem cell transplantation, CAR-T cell therapy and small molecule inhibitors have also emerged to treat sAML.

Acid Ceramidase Inhibitor LCL-805 Antagonizes Akt Signaling and Promotes Iron-Dependent Cell Death in Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is an aggressive hematologic malignancy requiring urgent treatment advancements. Ceramide is a cell-death-promoting signaling lipid that plays a central role in therapy-induced cell death. We previously determined that acid ceramidase (AC), a ceramide-depleting enzyme, is overexpressed in AML and promotes leukemic survival and drug resistance. The ceramidase inhibitor B-13 and next-generation lysosomal-localizing derivatives termed dimethylglycine (DMG)-B-13 prodrugs have been developed but remain untested in AML. Here, we report the in vitro anti-leukemic efficacy and mechanism of DMG-B-13 prodrug LCL-805 across AML cell lines and primary patient samples. LCL-805 inhibited AC enzymatic activity, increased total ceramides, and reduced sphingosine levels. A median EC50 value of 11.7 µM was achieved for LCL-805 in cell viability assays across 32 human AML cell lines. As a single agent tested across a panel of 71 primary AML patient samples, a median EC50 value of 15.8 µM was achieved. Exogenous ceramide supplementation with C6-ceramide nanoliposomes, which is entering phase I/II clinical trial for relapsed/refractory AML, significantly enhanced LCL-805 killing. Mechanistically, LCL-805 antagonized Akt signaling and led to iron-dependent cell death distinct from canonical ferroptosis. These findings elucidated key factors involved in LCL-805 cytotoxicity and demonstrated the potency of combining AC inhibition with exogenous ceramide.

Acid Ceramidase Inhibitor LCL-805 Antagonizes Akt Signaling and Promotes Iron-Dependent Cell Death in Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is an aggressive hematologic malignancy requiring urgent treatment advancements. Ceramide is a cell death-promoting signaling lipid that plays a central role in therapy-induced cell death. Acid ceramidase (AC), a ceramide-depleting enzyme, is overexpressed in AML and promotes leukemic survival and drug resistance. The ceramidase inhibitor B-13 and next-generation lysosomal-localizing derivatives termed dimethylglycine (DMG)-B-13 prodrugs have been developed but remain untested in AML. Here, we report the in vitro anti-leukemic efficacy and mechanism of DMG-B-13 prodrug, LCL-805, across AML cell lines and primary patient samples. LCL-805 inhibited AC enzymatic activity, increased total ceramides, and reduced sphingosine levels. A median EC50 value of 11.7 µM was achieved for LCL-805 in cell viability assays across 32 human AML cell lines. As a single agent tested across a panel of 71 primary AML patient samples, a median EC50 value of 15.8 µM was achieved. Exogenous ceramide supplementation with C6-ceramide nanoliposomes, which is entering phase I/II clinical trial for relapsed/refractory AML, significantly enhanced LCL-805 killing. Mechanistically, LCL-805 antagonized Akt signaling and led to iron-dependent cell death distinct from canonical ferroptosis. These findings elucidated key factors involved in LCL-805 cytotoxicity and demonstrated the potency of combining AC inhibition with exogenous ceramide.

Characterization of Anticancer Effects of the Analogs of DJ4, a Novel Selective Inhibitor of ROCK and MRCK Kinases.

The Rho associated coiled-coil containing protein kinase (ROCK1 and ROCK2) and myotonic dystrophy-related Cdc-42 binding kinases (MRCKα and MRCKß) are critical regulators of cell proliferation and cell plasticity, a process intimately involved in cancer cell migration and invasion. Previously, we reported the discovery of a novel small molecule (DJ4) selective multi-kinase inhibitor of ROCK1/2 and MRCKα/ß. Herein, we further characterized the anti-proliferative and apoptotic effects of DJ4 in non-small cell lung cancer and triple-negative breast cancer cells. To further optimize the ROCK/MRCK inhibitory potency of DJ4, we generated a library of 27 analogs. Among the various structural modifications, we identified four additional active analogs with enhanced ROCK/MRCK inhibitory potency. The anti-proliferative and cell cycle inhibitory effects of the active analogs were examined in non-small cell lung cancer, breast cancer, and melanoma cell lines. The anti-proliferative effectiveness of DJ4 and the active analogs was further demonstrated against a wide array of cancer cell types using the NCI-60 human cancer cell line panel. Lastly, these new analogs were tested for anti-migratory effects in highly invasive MDA-MB-231 breast cancer cells. Together, our results demonstrate that selective inhibitors of ROCK1/2 (DJE4, DJ-Allyl) inhibited cell proliferation and induced cell cycle arrest at G2/M but were less effective in cell death induction compared with dual ROCK1/2 and MRCKα/ß (DJ4 and DJ110).

Simultaneous Inhibition of Ceramide Hydrolysis and Glycosylation Synergizes to Corrupt Mitochondrial Respiration and Signal Caspase Driven Cell Death in Drug-Resistant Acute Myeloid Leukemia.

Acute myelogenous leukemia (AML), the most prevalent acute and aggressive leukemia diagnosed in adults, often recurs as a difficult-to-treat, chemotherapy-resistant disease. Because chemotherapy resistance is a major obstacle to successful treatment, novel therapeutic intervention is needed. Upregulated ceramide clearance via accelerated hydrolysis and glycosylation has been shown to be an element in chemotherapy-resistant AML, a problem considering the crucial role ceramide plays in eliciting apoptosis. Herein we employed agents that block ceramide clearance to determine if such a "reset" would be of therapeutic benefit. SACLAC was utilized to limit ceramide hydrolysis, and D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (D-threo-PDMP) was used to block the glycosylation route. The SACLAC D-threo-PDMP inhibitor combination was synergistically cytotoxic in drug-resistant, P-glycoprotein-expressing (P-gp) AML but not in wt, P-gp-poor cells. Interestingly, P-gp antagonists that can limit ceramide glycosylation via depression of glucosylceramide transit also synergized with SACLAC, suggesting a paradoxical role for P-gp in the implementation of cell death. Mechanistically, cell death was accompanied by a complete drop in ceramide glycosylation, concomitant, striking increases in all molecular species of ceramide, diminished sphingosine 1-phosphate levels, resounding declines in mitochondrial respiratory kinetics, altered Akt, pGSK-3ß, and Mcl-1 expression, and caspase activation. Although ceramide was generated in wt cells upon inhibitor exposure, mitochondrial respiration was not corrupted, suggestive of mitochondrial vulnerability in the drug-resistant phenotype, a potential therapeutic avenue. The inhibitor regimen showed efficacy in an in vivo model and in primary AML cells from patients. These results support the implementation of SL enzyme targeting to limit ceramide clearance as a therapeutic strategy in chemotherapy-resistant AML, inclusive of a novel indication for the use of P-gp antagonists.

Tuning between Nuclear Organization and Functionality in Health and Disease.

The organization of eukaryotic genome in the nucleus, a double-membraned organelle separated from the cytoplasm, is highly complex and dynamic. The functional architecture of the nucleus is confined by the layers of internal and cytoplasmic elements, including chromatin organization, nuclear envelope associated proteome and transport, nuclear-cytoskeletal contacts, and the mechano-regulatory signaling cascades. The size and morphology of the nucleus could impose a significant impact on nuclear mechanics, chromatin organization, gene expression, cell functionality and disease development. The maintenance of nuclear organization during genetic or physical perturbation is crucial for the viability and lifespan of the cell. Abnormal nuclear envelope morphologies, such as invagination and blebbing, have functional implications in several human disorders, including cancer, accelerated aging, thyroid disorders, and different types of neuro-muscular diseases. Despite the evident interplay between nuclear structure and nuclear function, our knowledge about the underlying molecular mechanisms for regulation of nuclear morphology and cell functionality during health and illness is rather poor. This review highlights the essential nuclear, cellular, and extracellular components that govern the organization of nuclei and functional consequences associated with nuclear morphometric aberrations. Finally, we discuss the recent developments with diagnostic and therapeutic implications targeting nuclear morphology in health and disease.

Ceramide nanoliposomes augment the efficacy of venetoclax and cytarabine in models of acute myeloid leukemia.

Despite several new therapeutic options for acute myeloid leukemia (AML), disease relapse remains a significant challenge. We have previously demonstrated that augmenting ceramides can counter various drug-resistance mechanisms, leading to enhanced cell death in cancer cells and extended survival in animal models. Using a nanoscale delivery system for ceramide (ceramide nanoliposomes, CNL), we investigated the effect of CNL within a standard of care venetoclax/cytarabine (Ara-C) regimen. We demonstrate that CNL augmented the efficacy of venetoclax/cytarabine in in vitro, ex vivo, and in vivo models of AML. CNL treatment induced non-apoptotic cytotoxicity, and augmented cell death induced by Ara-C and venetoclax. Mechanistically, CNL reduced both venetoclax (Mcl-1) and cytarabine (Chk1) drug-resistant signaling pathways. Moreover, venetoclax and Ara-C augmented the generation of endogenous pro-death ceramide species, which was intensified with CNL. Taken together, CNL has the potential to be utilized as an adjuvant therapy to improve outcomes, potentially extending survival, in patients with AML.

Therapeutic Benefits of Selenium in Hematological Malignancies.

Supplementing chemotherapy and radiotherapy with selenium has been shown to have benefits against various cancers. This approach has also been shown to alleviate the side effects associated with standard cancer therapies and improve the quality of life in patients. In addition, selenium levels in patients have been correlated with various cancers and have served as a diagnostic marker to track the efficiency of treatments or to determine whether these selenium levels cause or are a result of the disease. This concise review presents a survey of the selenium-based literature, with a focus on hematological malignancies, to demonstrate the significant impact of selenium in different cancers. The anti-cancer mechanisms and signaling pathways regulated by selenium, which impart its efficacious properties, are discussed. An outlook into the relationship between selenium and cancer is highlighted to guide future cancer therapy development.

ABHD11-AS1: An Emerging Long Non-Coding RNA (lncRNA) with Clinical Significance in Human Malignancies.

The aberrant expression of lncRNAs has been linked to the development and progression of different cancers. One such lncRNA is ABHD11 antisense RNA 1 (ABHD11-AS1), which has recently gained attention for its significant role in human malignancies. ABHD11-AS1 is highly expressed in gastric, lung, breast, colorectal, thyroid, pancreas, ovary, endometrium, cervix, and bladder cancers. Several reports highlighted the clinical significance of ABHD11-AS1 in prognosis, diagnosis, prediction of cancer progression stage, and treatment response. Significantly, the levels of ABHD11-AS1 in gastric juice had been exhibited as a clinical biomarker for the assessment of gastric cancer, while its serum levels have prognostic potential in thyroid cancers. The ABHD11-AS1 has been reported to exert oncogenic effects by sponging different microRNAs (miRNAs), altering signaling pathways such as PI3K/Akt, epigenetic mechanisms, and N6-methyladenosine (m6A) RNA modification. In contrast, the mouse homolog of AHD11-AS1 (Abhd11os) overexpression had exhibited neuroprotective effects against mutant huntingtin-induced toxicity. Considering the emerging research reports, the authors attempted in this first review on ABHD11-AS1 to summarize and highlight its oncogenic potential and clinical significance in different human cancers. Lastly, we underlined the necessity for future mechanistic studies to unravel the role of ABHD11-AS1 in tumor development, prognosis, progression, and targeted therapeutic approaches.

Acute Myeloid Leukemia Stem Cells: Origin, Characteristics, and Clinical Implications.

The stem cells of acute myeloid leukemia (AML) are the malignancy initiating cells whose survival ultimately drives growth of these lethal diseases. Here we review leukemia stem cell (LSC) biology, particularly as it relates to the very heterogeneous nature of AML and to its high disease relapse rate. Leukemia ontogeny is presented, and the defining functional and phenotypic features of LSCs are explored. Surface and metabolic phenotypes of these cells are described, particularly those that allow distinction from features of normal hematopoietic stem cells (HSCs). Opportunities for use of this information for improving therapy for this challenging group of diseases is highlighted, and we explore the clinical needs which may be addressed by emerging LSC data. Finally, we discuss current gaps in the scientific understanding of LSCs.

Engineered Probiotic and Prebiotic Nutraceutical Supplementations in Combating Non-communicable Disorders: A Review.

Nutritional supplementations are a form of nutrition sources that may help in improving the health complexities of a person throughout his or her life span. Being also categorized as food supplementations, nutraceuticals are products that are extracted from edible sources with medical benefits as well as primary nutritional values. Nutraceuticals can be considered as functional foods. There are evidences that nutraceutical supplementations can alter the commensal gut microbiota and help to prevent or fight against chronic non-communicable degenerative diseases in adults, including neurological disorders (Autism Spectrum Disorder [ASD], Parkinson's disease [PD], Multiple sclerosis [MS]) and metabolic disorders (Type-II diabetes, obesity and non-alcoholic fatty liver disease). They can even lessen the complexities of preterm babies like extra-uterine growth restriction, necrotizing enterocolitis, infant eczema and allergy (during pregnancy) as well as bronchopulmonary dysplasia. Molecular perception of inflammatory and apoptotic modulators regulating the pathogenesis of these health risks, their control and management by probiotics and prebiotics could further emphasize the scientific overview of their utility. In this study, the pivotal role of nutraceutical supplementations in regulating or modulating molecular pathways in the above non-communicable diseases is briefly described. This work also gives an overall introduction of the sophisticated genome-editing techniques and advanced delivery systems in therapeutic activities applicable under these health risks.

DJ4 Targets the Rho-Associated Protein Kinase Pathway and Attenuates Disease Progression in Preclinical Murine Models of Acute Myeloid Leukemia.

The poor prognosis of acute myeloid leukemia (AML) and the highly heterogenous nature of the disease motivates targeted gene therapeutic investigations. Rho-associated protein kinases (ROCKs) are crucial for various actin cytoskeletal changes, which have established malignant consequences in various cancers, yet are still not being successfully utilized clinically towards cancer treatment. This work establishes the therapeutic activity of ROCK inhibitor (5Z)-2-5-(1H-pyrrolo[2,3-b]pyridine-3-ylmethylene)-1,3-thiazol-4(5H)-one (DJ4) in both in vitro and in vivo preclinical models of AML to highlight the potential of this class of inhibitors. Herein, DJ4 induced cytotoxic and proapoptotic effects in a dose-dependent manner in human AML cell lines (IC50: 0.05-1.68 µM) and primary patient cells (IC50: 0.264-13.43 µM); however, normal hematopoietic cells were largely spared. ROCK inhibition by DJ4 disrupts the phosphorylation of downstream targets, myosin light chain (MLC2) and myosin-binding subunit of MLC phosphatase (MYPT), yielding a potent yet selective treatment response at micromolar concentrations, from 0.02 to 1 µM. Murine models injected with luciferase-expressing leukemia cell lines subcutaneously or intravenously and treated with DJ4 exhibited an increase in overall survival and reduction in disease progression relative to the vehicle-treated control mice. Overall, DJ4 is a promising candidate to utilize in future investigations to advance the current AML therapy.

Identification of Histone H3 and H4 Amino Acid Residues Important for the Regulation of Arsenite Stress Signaling in Saccharomyces cerevisiae.

Arsenic is an environmental carcinogen that causes many diseases in humans, including cancers and organ failures, affecting millions of people in the world. Arsenic trioxide is a drug used for the treatment of acute promyelocytic leukemia (APL). In the present study, we screened the synthetic histone H3 and H4 library in the presence of arsenite to understand the role of histone residues in arsenic toxicity. We identified residues of histone H3 and H4 crucial for arsenite stress response. The residues H3T3, H3G90, H4K5, H4G13, and H4R95 are required for the activation of Hog1 kinase in response to arsenite exposure. We showed that a reduced level of Hog1 activation increases the intracellular arsenic content in these histone mutants through the Fps1 channel. We have also noticed the reduced expression of ACR3 exporter in the mutants. The growth defect of mutants caused by arsenite exposure was suppressed in hyperosmotic conditions, in a higher concentration of glucose, and upon deletion of the FPS1 gene. The arsenite sensitive histone mutants also showed a lack of H3K4 methylation and reduced H4K16 acetylation. Altogether, we have identified the key residues in histone H3 and H4 proteins important for the regulation of Hog1 signaling, Fps1 activity, and ACR3 expression during arsenite stress.

Previously uncharacterized amino acid residues in histone H3 and H4 mutants with roles in DNA damage repair response and cellular aging.

Chromatin regulates gene expression and genome maintenance, and consists of histones and other components. The post-translational modification of histones plays a key role in maintaining the structure and function of chromatin under different pathophysiological stress conditions. Here, we investigate the functions of previously unexplored amino acid residues in histones H3 and H4. To do so, we screened a library of yeast histone mutants following DNA damage and identified that substitution mutations of histone H3 (H3Q5A/E and H3Q120A) and H4 (H4Y88A/E and H4R78K) render yeast cells sensitive to DNA-damaging agents. These histone mutants show an activated DNA damage response, Rad53 phosphorylation and Sml1 degradation in the presence of methyl methanesulfonate (MMS). In histone H3Q5A/E mutants, RNR2 and RNR3 genes were induced at low level, as was RNR3 in H4 histone mutants following DNA damage. In H3 mutant cells, the cell cycle was deregulated, leading to inefficient cell cycle arrest in the presence of MMS, and genes involved in aging and DNA damage repair pathways were constitutively upregulated. In H3 mutants (H3Q5A, H3Q5E and H3Q120A), we observed reduced chronological lifespan (CLS), compared with extended CLS in the H4R78K mutant. Histone mutants also showed altered H3K4me and H3K56ac modifications and improper activation of the stress responsive Slt2 and Hog1 kinases. Thus, we have determined the significance of previously uncharacterized residues of H3 and H4 in DNA damage response, cell cycle progression and cellular aging.

A systematic assessment of chemical, genetic, and epigenetic factors influencing the activity of anticancer drug KP1019 (FFC14A).

KP1019 ([trans-RuCl4(1H-indazole)2]; FFC14A) is one of the promising ruthenium-based anticancer drugs undergoing clinical trials. Despite the pre-clinical and clinical success of KP1019, the mode of action and various factors capable of modulating its effects are largely unknown. Here, we used transcriptomics and genetic screening approaches in budding yeast model and deciphered various genetic targets and plethora of cellular pathways including cellular signaling, metal homeostasis, vacuolar transport, and lipid homeostasis that are primarily targeted by KP1019. We also demonstrated that KP1019 modulates the effects of TOR (target of rapamycin) signaling pathway and induces accumulation of neutral lipids (lipid droplets) in both yeast and HeLa cells. Interestingly, KP1019-mediated effects were found augmented with metal ions (Al3+/Ca2+/Cd2+/Cu2+/Mn2+/Na+/Zn2+), and neutralized by Fe2+, antioxidants, osmotic stabilizer, and ethanolamine. Additionally, our comprehensive screening of yeast histone H3/H4 mutant library revealed several histone residues that could significantly modulate the KP1019-induced toxicity. Altogether, our findings in both the yeast and HeLa cells provide molecular insights into mechanisms of action of KP1019 and various factors (chemical/genetic/epigenetic) that can alter the therapeutic efficiency of this clinically important anticancer drug.

Sen1, the homolog of human Senataxin, is critical for cell survival through regulation of redox homeostasis, mitochondrial function, and the TOR pathway in Saccharomyces cerevisiae.

Mutations in the Senataxin gene, SETX are known to cause the neurodegenerative disorders, ataxia with oculomotor apraxia type 2 (AOA2), and amyotrophic lateral sclerosis 4 (ALS4). However, the mechanism underlying disease pathogenesis is still unclear. The Senataxin N-terminal protein-interaction and C-terminal RNA/DNA helicase domains are conserved in the Saccharomyces cerevisiae homolog, Sen1p. Using genome-wide expression analysis, we first show alterations in key cellular pathways such as: redox, unfolded protein response, and TOR in the yeast sen1 ΔN mutant (N-terminal truncation). This mutant exhibited growth defects on nonfermentable carbon sources, was sensitive to oxidative stress, and showed severe loss of mitochondrial DNA. The growth defect could be partially rescued upon supplementation with reducing agents and antioxidants. Furthermore, the mutant showed higher levels of reactive oxygen species, lower UPR activity, and alterations in mitochondrial membrane potential, increase in vacuole acidity, free calcium ions in the cytosol, and resistance to rapamycin treatment. Notably, the sen1 ∆N mutant showed increased cell death and shortened chronological life span. Given the strong similarity of the yeast and human Sen1 proteins, our study thus provides a mechanism for the progressive neurological disorders associated with mutations in human senataxin.

Combined Transcriptomics and Chemical-Genetics Reveal Molecular Mode of Action of Valproic acid, an Anticancer Molecule using Budding Yeast Model.

Valproic acid (VA) is a pharmacologically important histone deacetylase inhibitor that recently garnered attention as an anticancer agent. Since the molecular mechanisms behind the multiple effects of VA are unclear, this study was aimed to unravel the comprehensive cellular processes affected by VA and its molecular targets in vivo using budding yeast as a model organism. Interestingly, genome-wide transcriptome analysis of cells treated with VA showed differential regulation of 30% of the genome. Functional enrichment analysis of VA transcriptome evidenced alteration of various cellular processes including cell cycle, cell wall biogenesis, DNA repair, ion homeostasis, metabolism, stress response, transport and ribosomal biogenesis, etc. Moreover, our genetic screening analysis revealed VA molecular targets belonging to oxidative and osmotic stress, DNA repair, cell wall integrity, and iron homeostasis. Further, our results demonstrated the activation of mitogen-activated protein kinases (MAPKs) Hog1 (p38) and Slt2 (p44/42) upon VA treatment. Our results also exhibited that VA acts through alteration of mitochondrial, ER architecture and functions. Especially, VA effects were neutralized in cells lacking lipid particles. Altogether, our results deciphered the novel molecular insights and mechanistic links to strengthen our knowledge on diverse cellular effects of VA along with its probable therapeutic targets and detoxification approaches.

Synthesis, structure, magnetic and biological activity studies of bis-hydrazone derived Cu(ii) and Co(ii) coordination compounds.

Four coordination compounds of formulae [Cu(II)2(H2L(1))(HL(1))](ClO4)3·H2O (1), [Cu(II)2(H2L(2))(CH3OH)2](ClO4)2·2CH3OH (2), [Co(II)2(H2L(1))2](ClO4)4 (3) and [Co(II)2(H2L(2))2]·2H2O (4) were synthesized via self-assembly of succinohydrazone derived ligands (H2L(1) = N',N'-4-bis(2-pyridyl)succinohydrazide, H4L(2) = N',N'-4-bis(2-hydroxybenzylidene)succinohydrazide) and Cu(2+) and Co(2+) ions, respectively. The compounds were characterized by crystal structure determination, magnetic measurements and biological activities. Compounds 1, 3 and 4 have discrete double helicate structures, whereas compound 2 is a one-dimensional chain. Magnetic studies show antiferromagnetic exchange interactions in 2 with a J value of -67.1 cm(-1) and antiferromagnetic spin-canting in compound 3 originates through supramolecular H-bonding. For compound 3, a clear bifurcation was observed in zero field cooled (ZFC) and field cooled (FC) measurement at a temperature of 3.5 K and field of 0.1 T, implying long range magnetic ordering below this temperature. Interestingly, all of compounds 1-4 show significant changes in their absorption (hypo- and hyperchromism) in the presence of SS-DNA, inferring interaction between the compounds and DNA. In addition, compounds 1-4 significantly exhibited nuclease activities on both RNA and pUC19 plasmid DNA. Moreover, the nuclease activity was further enhanced in the presence of oxidant (H2O2) and suggests the possible role of reactive oxygen species in DNA nicking ability of compounds 1-4. Furthermore, compounds 1, 2 and 4 exhibited significant cytotoxicity against mammalian cancer cell lines (HeLa, A549 and MDAMB-231). In addition, our results from Annexin/PI staining and DNA fragmentation assays revealed that these compounds are capable of inducing apoptosis and have potential to act as anticancer drugs.