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Vanadium compounds are well known for their therapeutic interventions against several diseases. Various biochemical attributes of vanadium complexes inspired us to evaluate the cancer cell killing efficacy of the vanadium complex, viz., vanadyl N-(2-hydroxyacetophenone) glycinate [VO(NG) 2 ]. Previously we showed that VO(NG) 2 is an effective anticancer agent in in vitro and in vivo cancer models and imposed miniscule side effects. Herein we report that VO(NG) 2 is significantly cytotoxic to various cancer cell lines. Furthermore, this redox active vanadyl complex altered the redox homeostatsis of many human cancer cell lines significantly. VO(NG) 2 actuates programmed cell death in human colorectal carcinoma cells(HCT-116) through mitochondrial outer membrane permeabilization but in caspase independent manner, possibly by altering cellular redox status and by inflicting DNA damage. Thus, the present work is an attempt to provide many evidences regarding the potent and selective chemotherapeutic efficacy of the novel VO(NG) 2 ., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Background: Development of novel strategies to kill cancer by sparing normal cells is of utmost importance. Apart from their known antimicrobial activity, only limited information has been recorded regarding the antitumor potential of biocompatible silver oxide nanoparticles (AgONPs). There is a need to evaluate the anticancer potential of biocompatible AgONPs in vitro., Methods: A new approach of utilizing the leaf extract of Excoecaria agallocha was used to synthesize AgONPs. This was then characterized by ultraviolet-visible spectrophotometry, nanoparticle-tracking analysis, and ζ-potential analysis. Cytotoxicity and apoptotic potential were evaluated with an MTT assay and an annexin V-binding assay against the murine melanoma (B16F10), murine colon cancer (CT26), murine lung adenocarcinoma (3LL), and murine Ehrlich ascites carcinoma (EAC) cell lines. Cellular localization of AgONPs was evaluated on fluorescence microscopy., Results: UV peaks at 270 and 330 nm indicated the formation of nanoparticles (NPs) and the NP-tracking analyzer revealed them to have a size of 228 nm. AgONPs exerted initial cytotoxicity, specifically against all the experimental malignant cells by sparing the normal cell lines. Moreover, AgONPs exert apoptosis equally on all the malignant cells in vitro and ex vivo. This cytotoxicity possibly occurs via the nuclear translocation of AgONPs as analyzed in B16F10 cells., Conclusions: AgONPs utilizing natural sources would be a new medicinal approach against a broad spectrum of malignancy., (© 2017 S. Karger AG, Basel.)

Multidrug resistance (MDR) in cancer represents a variety of strategies employed by tumor cells to evade the beneficial cytotoxic effects of structurally different anticancer drugs and thus confers impediments to the successful treatment of cancers. Efflux of drugs by MDR protein-1, functional P-glycoprotein and elevated level of reduced glutathione confer resistance to cell death or apoptosis and thus provide a possible therapeutic target for overcoming MDR in cancer. Previously, we reported that a Schiff base ligand, potassium-N-(2-hydroxy 3-methoxy-benzaldehyde)-alaninate (PHMBA) overcomes MDR in both in vivo and in vitro by targeting intrinsic apoptotic/necrotic pathway through induction of reactive oxygen species (ROS). The present study describes the synthesis and spectroscopic characterization of a copper chelate of Schiff base, viz., copper (II)-N-(2-hydroxy-3-methoxy-benzaldehyde)-alaninate (CuPHMBA) and the underlying mechanism of cell death induced by CuPHMBA in vitro. CuPHMBA kills both the drug-resistant and sensitive cell types irrespective of their drug resistance phenotype. The cell death induced by CuPHMBA follows apoptotic pathway and moreover, the cell death is associated with intrinsic mitochondrial and extrinsic receptor-mediated pathways. Oxidative stress plays a pivotal role in the process as proved by the fact that antioxidant enzyme; polyethylene glycol conjugated-catalase completely blocked CuPHMBA-induced ROS generation and abrogated cell death. To summarize, the present work provides a compelling rationale for the future clinical use of CuPHMBA, a redox active copper chelate in the treatment of cancer patients, irrespective of their drug-resistance status.

Myeloid-derived suppressor cells (MDSCs), one of the major orchestrators of immunosuppressive network are present in the tumor microenvironment suppress antitumor immunity by subverting Th1 response in tumor site and considered as a great obstacle for advancement of different cancer immunotherapeutic protocols. Till date, various pharmacological approaches have been explored to modulate the suppressive functions of MDSCs in vivo. The present study describes our endeavor to explore a possibility of eradicating MDSCs by the application of a copper chelate, namely copper N-(2-hydroxy acetophenone) glycinate (CuNG), previously found to be a potential immunomodulator that can elicit antitumorogenic Th1 response in doxorubicin-resistant EAC (EAC/Dox) bearing mice. Herein, we demonstrated that CuNG treatment could reduce Gr-1+CD11b+ MDSC accumulation in ascitic fluid and spleen of EAC/Dox tumor model. Furthermore, we found that CuNG mediated reduction in MDSCs is associated with induction of Th1 response and reduction in Treg cells. Moreover, we observed that CuNG could deplete MDSCs by inducing Fas-FasL mediated apoptotic cell death where death receptor Fas expression is enhanced in MDSCs and FasL is provided by activated T cells. However, MDSC expansion from bone marrow cells and their differentiation was not affected by CuNG. Altogether, these findings suggest that the immunomodulatory property of CuNG is attributed to, at least in part, by its selective cytotoxic action on MDSCs. So, this preclinical study unveils a new mechanism of regulating MDSC levels in drug-resistant cancer model and holds promise of translating the findings into clinical settings.

Anticancer drugs induce apoptosis to cancer cells and also exhibit undesired toxicity to normal cells. Therefore development of novel agents triggering apoptosis and have low toxicity towards normal cells is most important. Hydroxamic acids suppress tumour cell growth through apoptosis but the underlying mechanism is poorly understood. Herein, we describe the apoptotic potential of a dibasic hydroxamic acid derivative, viz., oxayl bis (N-phenyl) hydroxamic acid (OBPHA), which induces apoptosis through generation of both ROS and NO in doxorubicin resistant T-lymphoblastic leukemia, CEM/ADR5000 cells. Present study discloses that OBPHA selectively kills cancerous cells irrespective of their drug resistant phenotype. We also determined the crystal structure of OBPHA to understand the structural requirements for apoptosis; the study reveals that the presence of substituted hydroxamic acid groups (-CO-NH-OH) favours the generation of NO possibly through auto degeneration. Along with the induction of caspase 3 mediated intrinsic apoptosis; OBPHA also activates p53 dependent signalling cascade and downregulates HDAC3 expression in a time dependent manner possibly due to increased ROS and NO production and simultaneous decrease in cellular GSH level. Thus ROS and NO mediated downstream signalling are essential for the anticancer effect of OBPHA. Therefore OBPHA, having a structurally relevant pharmacophore provides important insight into the development of new ROS and RNS generating chemicals inducing p53 dependent apoptosis., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Background: Multidrug resistance (MDR) is a major problem in cancer treatment. Cu complexes possess the ability to overcome MDR in cancer. Therefore, the search for new Cu complexes is of great clinical significance and we address the anticancer effects of a previously synthesized novel 9-phenyldibenzo[a,c]phenazin-9-ium cation [1(+)] as [1] [CuCl2] and as [1] [I]., Methods: The existence of the monovalent Cu(I) in [1] [CuCl2] was proven by electron paramagnetic resonance (EPR) studies and in vivo anticancer effects were studied in animals., Results: The monovalent nature of the Cu ion in [1] [CuCl2] was determined through EPR. The mean survival time of mice bearing doxorubicin-resistant Ehrlich ascites carcinoma cells is longer when [1] [I] is injected intraperitoneally whereas [1] [CuCl2] does not significantly increase the median survival in tumor-bearing mice. Compounds do not follow the immunomodulatory route and only [1] [I] shows cytotoxic activity in both MDR and drug-sensitive leukemia cell lines., Conclusion: An organic iodide complex rather than a cupric complex possesses direct cytotoxic potential., (© 2015 S. Karger AG, Basel.)

Drug induced toxicity and drug resistance are the major impediments to successful application of cancer chemotherapy. Therefore, selective targeting of the key biochemical events of the malignant cells may have a great therapeutic potential in specifically kill the cancer cells. We have evaluated in vitro the cytotoxic efficacy of a previously reported copper complex viz. copper N-(2-hydroxy acetophenone) glycinate (CuNG) on different drug sensitive and resistant cancer cell lines by MTT, annexin V positivity and caspase 3 activation assays. We have also investigated the underlying signalling events in CuNG mediated apoptosis of cancer cells by Western blotting technique. We have found that CuNG preferentially induces apoptosis to malignant cells irrespective of drug sensitivity and spares the normal cells. Our studies disclose that CuNG causes cellular redox imbalance in cancer cells through depletion of intracellular GSH level. CuNG mediated depletion of intracellular GSH level induces mitochondrial superoxide generation, which detaches cyto C from mitochondrial membrane through lipid peroxidation. The detached cyto C then release into the extra mitochondrial milieu in Bax mediated pathway where CuNG facilitates the binding of Bax through dissociation of hexokinase II from mitochondrial membrane. The present study opens the possibility of developing effective chemotherapeutic drugs by synthesizing numerous chemical compounds capable of targeting cellular redox environment and thus specifically kills cancer cells of broad spectrum.

Multidrug resistance-associated protein 1 (MRP1) reduces intracellular anticancer drug accumulation either by co transporting them with glutathione (GSH) or extruding drug-GSH conjugates outside of the cell. Thus, MRP1 confers multidrug resistance (MDR) and worsen successful chemotherapeutic treatment against cancer. Although the exact mechanism of MRP1 involved in MDR remains unknown, the elevated level of intracellular GSH is considered as a key factor responsible for MDR in cancer. Hence the quest for non-toxic molecules that are able to deplete intracellular GSH has profound importance to subdue MDR. The present preclinical study depicts the resistance reversal potentiality of an iron complex; viz. Ferrous N-(2-hydroxy acetophenone) glycinate (FeNG) developed by us in doxorubicin resistant Ehrlich ascites carcinoma (EAC/Dox) cells. FeNG potentiate cytotoxic effect of doxorubicin on EAC/Dox cells ex vivo and also increases the survivability EAC/Dox bearing Swiss albino mice in vivo as well. Moreover, in vivo administration of FeNG significantly depletes intracellular GSH with ensuant increase in doxorubicin concentration in EAC/Dox cells without alternation of MRP1 expression. In addition, intra-peritoneal (i.p.) application of FeNG in normal or EAC/Dox bearing mice does not cause any systemic toxicity in preliminary trials in mouse Ehrlich ascites carcinoma model. Therefore, the present report provides evidence that FeNG may be a promising new resistance modifying agent against drug resistant cancers.

Multiple drug resistance (MDR) remains a major clinical challenge for cancer treatment. P-glycoprotein is the major contributor and they exceed their role in the chemotherapy resistance of most of the malignancies. Attempts in several preclinical and clinical studies to reverse the MDR phenomenon by using MDR modulators have not yet generated promising results. In the present study, a co-ordination complex of zinc viz., Zn N-(2-hydroxyacetophenone)glycinate (ZnNG) has been synthesized, characterized and its antitumour activity was tested in vitro against drug sensitive and resistant human T-lymphoblastic leukemic cell lines (CCRF/CEM and CEM/ADR5000 respectively) and in vivo against Ehrlich ascites carcinoma (EAC) implanted in female Swiss albino mice. To evaluate the cytotoxic potential of ZnNG, we used sensitive CCRF/CEM and drug resistant CEM/ADR 5000 cell lines in vitro. Moreover, ZnNG also has the potential ability to reverse the multidrug resistance phenotype in drug resistant CEM/ADR 5000 cell line and induces apoptosis in combination with vinblastine. ZnNG remarkably increases the life span of Swiss albino mice bearing sensitive and doxorubicin resistant subline of EAC in presence and in absence of doxorubicin. In addition, intraperitoneal application of ZnNG in mice does not show any systemic toxicity in preliminary trials in normal mice. To conclude, a novel metal chelate of zinc viz., ZnNG, may be a promising therapeutic agent against sensitive as well as drug resistant cancers.

Multidrug resistance (MDR) mediated by the over expression of drug efflux protein P-glycoprotein (P-gp) is one of the major impediments to successful treatment of cancer. P-gp acts as an energy-dependent drug efflux pump and reduces the intracellular concentration of structurally unrelated drugs inside the cells. Therefore, there is an urgent need for development of new compound that are less toxic and effective against drug resistance in cancer. Preclinical studies have shown that quinoline derivatives possess anticancer activities. Here, we report the antitumor potential of quinoline derivative, 2-(2-Methyl-quinolin-4ylamino)-N-phenyl acetamide (S4). To evaluate the cytotoxic potential of S4, we used four different cell lines (Hela, HCT-116, CCRF-CEM, and CEM/ADR 5000) in vitro, and showed that S4 kills doxorubicin resistant T lymphoblastic leukemia cell, CEM/ADR 5000 in a concentration dependent manner while others remains unaffected. Moreover, S4 induces apoptosis in CEM/ADR 5000 cells through generation reactive oxygen species (ROS). This is substantiated by the fact that the antioxidant N-acetyle-cysteine (NAC) completely blocks ROS generation and, subsequently, abrogates S4 induced apoptosis. Furthermore, in vivo treatment with S4 significantly increases the life span of swiss albino mice bearing sensitive and doxorubicin resistant subline of Ehrlich ascites carcinoma. In addition, intraperitoneal application of S4 in mice does not show any systemic toxicity at concentrations that in preliminary trials in a mice Ehrlich ascites carcinoma model. Therefore, present report provides evidence that S4, a quinoline derivative, may be a promising new therapeutic agent against drug resistant cancers., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)

Cancer chemotherapy suffers from selectivity and undesired toxicity of the drugs. Since zinc is a biocompatible tracer element and cysteine derivatives are used in cancer chemoprevention, we intend to develop a complex of zinc and cysteine-derivatives as potent, non-toxic anticancer agents. Herein, we synthesized and characterized cysteine based ligand, 2-[(2-Hydroxy-3-methoxy-benzylidene)-amino]-3-mercapto-propionic acid and its Zn-complex, which are found to be non-toxic towards normal human PBMC. Data also revealed that only Zn-complex exhibited remarkable apoptosis in drug-sensitive CCRF-CEM and multidrug-resistant CEM/ADR5000 cancer cells as assessed by MTT, Cell cycle and AnnexinV binding assay. Moreover, Zn-complex altered ROS and GSH level of the respective cell lines. Finally, treatment of Zn-complex in Swiss albino mice did not show any systemic toxicity in preliminary trials in normal mice and remarkably increased the life-span of EAC bearing mice. In conclusion, the synthesized Zn-complex may be developed for efficacious, multidrug resistance reversal, non-toxic chemotherapeutic agents in future. [ABSTRACT FROM AUTHOR]

Background: Multidrug resistance (MDR) is a major problem in cancer treatment. Cu complexes possess the ability to overcome MDR in cancer. Therefore, the search for new Cu complexes is of great clinical significance and we address the anticancer effects of a previously synthesized novel 9-phenyldibenzo[a,c]phenazin-9-ium cation [1+] as [1] [CuCl2] and as [1] [I]. Methods: The existence of the monovalent Cu(I) in [1] [CuCl2] was proven by electron paramagnetic resonance (EPR) studies and in vivo anticancer effects were studied in animals. Results: The monovalent nature of the Cu ion in [1] [CuCl2] was determined through EPR. The mean survival time of mice bearing doxorubicin-resistant Ehrlich ascites carcinoma cells is longer when [1] [I] is injected intraperitoneally whereas [1] [CuCl2] does not significantly increase the median survival in tumor-bearing mice. Compounds do not follow the immunomodulatory route and only [1] [I] shows cytotoxic activity in both MDR and drug-sensitive leukemia cell lines. Conclusion: An organic iodide complex rather than a cupric complex possesses direct cytotoxic potential. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Chemotherapeutics are the sole treatment modality for cancer patients at advanced condition. In the pursuit of getting an efficient, selective and non toxic anticancer agent that has not been discovered yet, we rationally synthesized a vanadium complex with a Schiff base ligand N -(-2-hydroxyacetophenone) glycinate. Characterization of the synthesized complex VO(NG) 2 , was carried out with the help of various spectroscopic means. The complex proved to be a broad spectrum anticancer agent with significantly less toxicity towards normal cells as evident from cell viability assay. Furthermore, VO(NG) 2 treatment increased the life-span of ascitic and solid tumor bearing Swiss albino mice and did not show any significant symptomatic sub acute toxicity on normal Swiss albino mice. [ABSTRACT FROM AUTHOR]

Abstract: Drug resistance is a problem that hinders the numerous successes of chemotherapeutic intervention of cancer and continues to be a major obstacle for cures. Till date, several attempts have been made to develop suitable multidrug resistance (MDR) reversing agents. But, throughout the clinical development of MDR reversing agents, patients repeatedly suffer from toxicities. So far, some anticancer activity of Schiff bases which are the condensation products of carbonyl compounds and primary amines and their metal complexes has been described. But, overcoming multidrug resistance, by the use of such small molecules still remain unexplored. Under this backdrop, in search of less toxic and more effective MDR reversing agents our laboratory has developed the different metal chelates of Schiff base N-(2-hydroxy acetophenone)glycinate (NG) which is structurally similar to azatyrosine [L-β-(5-hydroxy-2-pyridyl)-alanine] that inhibits tumor formation by deactivating the c-Raf-1 kinase and c-Ha-ras signalling pathway. A decade-long research proposes possible strategies to overcome MDR by exploiting the chemical nature of such metal chelates. In this review we have catalogued the success of metal chelates of NG to overcome MDR in cancer. The review depict that the problem of MDR can be circumvent by synchronized activation of immunogenic cell death pathways that utilize the components of a host’s immune system to kill cancer cells in combination with other conventional strategies. The current wealth of preclinical information promises better understanding of the cellular processes underlying MDR reversing activity of metal derivatives of NG and thus exposes several cellular targets for rational designing of new generation of Schiff base metal chelates as MDR reversing agents. [Copyright &y& Elsevier]