Potential Anticancer Drug Target Research Articles

Anticancer Activity of in Silico Interaction Between Curcumin and Cyclooxygenase 2 Enzyme

In this research, the in silico interaction between curcumin and cyclooxygenase 2 (COX-2) was investigated using molecular docking with the AutoDock 4.0 software application. This study aimed to determine the pharmacokinetic profile of the compound, affinity, and exchange of curcumin with COX-2 inhibitors in silico. Curcumin’s interactions with COX-2 were compared to those of the known COXinhibitor, celecoxib. The pharmacodynamic test was used to show the free bond energy. Curcumin demonstrated anticancer activity by inhibiting the metabolism of arachidonic acid through the enzyme COX-2 and inhibiting free radicals in the enzymatic pathway. This was indicated by the value free energy (ΔG) of the curcumin compounds having a binding energy value of -8.81 kcal/mol, which is smaller than that of arachidonic acid (-5.20 kcal/mol). However, celecoxib had a more stable bond with the COX-2 inhibitors than curcumin, with a value of -10.11 kcal/mol. As a result, curcumin can be considered a suitable lead compound in developing new COX-2 inhibitors, which are a potential target for anticancer drugs.
 Keywords: curcumin, COX-2 inhibitor, anticancer

A miRNA-mediated attenuation of hepatocarcinogenesis in both hepatocytes and Kupffer cells

MicroRNAs (miRNAs) are small noncoding RNAs that regulate a variety of physiological and pathological functions. miR-26a is one of the many miRNAs that have been identified as regulators of cancer development and as potential anticancer drug targets. However, the specific cellular and molecular mechanisms by which miR-26a attenuates hepatocarcinogenesis are still elusive. Here, we interrogated mouse models with miR-26a cell-specific overexpression in either hepatocytes or myeloid cells to show that miR-26a strongly attenuated the chemical-induced hepatocellular carcinoma (HCC). miR-26a overexpression broadly inhibited the inflammatory response in both hepatocytes and macrophages by decreasing several key oncogenic signaling pathways in HCC promotion. These findings thus reveal new insights into a concerted role of miR-26a in both hepatocytes and Kupffer cells to suppress hepatocarcinogenesis, thereby highlighting the potential use of miR-26a mimetics as potential approaches for the prevention and treatment of HCC.

A redox-sensitive iron-sulfur cluster in murine FAM72A controls its ability to degrade the nuclear form of uracil-DNA glycosylase

Murine FAM72A, mFAM72A, binds the nuclear form of uracil-DNA glycosylase, mUNG2, inhibits its activity and causes its degradation. In immunoprecipitation assays the human paralog, hFAM72A, binds hUNG2 and is a potential anti-cancer drug target because of its high expression in many cancers. Using purified mFAM72A, and mUNG2 proteins we show that mFAM72A binds mUNG2, and the N-terminal 25 amino acids of mUNG2 bind mFAM72A at a nanomolar dissociation constant. We also show that mFAM72A is present throughout the cells, and mUNG2 helps localize it to nuclei. Based on in silico models of mFAM72A-mUNG2 interactions, we constructed several mutants of mFAM72A and found that while they have reduced ability to deplete mUNG2, the mutations also destabilized the former protein. We confirmed that Withaferin A, a predicted lead molecule for the design of FAM72A inhibitors, binds mFAM72A with micromolar affinity but has little affinity to mUNG2. We identified two potential metal-binding sites in mFAM72A and show that one of the sites contains an Fe-S cluster. This redox-sensitive cluster is involved in the mFAM72A-mUNG2 interaction and modulates mFAM72A activity. Hydrogen peroxide treatment of cells increases mUNG2 depletion in a FAM72A-dependent fashion suggesting that mFAM72A activity is redox-sensitive.

Loss of TIP60 (KAT5) abolishes H2AZ lysine 7 acetylation and causes p53, INK4A, and ARF-independent cell cycle arrest

Histone acetylation is essential for initiating and maintaining a permissive chromatin conformation and gene transcription. Dysregulation of histone acetylation can contribute to tumorigenesis and metastasis. Using inducible cre-recombinase and CRISPR/Cas9-mediated deletion, we investigated the roles of the histone lysine acetyltransferase TIP60 (KAT5/HTATIP) in human cells, mouse cells, and mouse embryos. We found that loss of TIP60 caused complete cell growth arrest. In the absence of TIP60, chromosomes failed to align in a metaphase plate during mitosis. In some TIP60 deleted cells, endoreplication occurred instead. In contrast, cell survival was not affected. Remarkably, the cell growth arrest caused by loss of TIP60 was independent of the tumor suppressors p53, INK4A and ARF. TIP60 was found to be essential for the acetylation of H2AZ, specifically at lysine 7. The mRNA levels of 6236 human and 8238 mouse genes, including many metabolism genes, were dependent on TIP60. Among the top 50 differentially expressed genes, over 90% were downregulated in cells lacking TIP60, supporting a role for TIP60 as a key co-activator of transcription. We propose a primary role of TIP60 in H2AZ lysine 7 acetylation and transcriptional activation, and that this fundamental role is essential for cell proliferation. Growth arrest independent of major tumor suppressors suggests TIP60 as a potential anti-cancer drug target.

An Integrated Mass Spectrometry-Based Glycomics-Driven Glycoproteomics Analytical Platform to Functionally Characterize Glycosylation Inhibitors.

Cancer progression is linked to aberrant protein glycosylation due to the overexpression of several glycosylation enzymes. These enzymes are underexploited as potential anticancer drug targets and the development of rapid-screening methods and identification of glycosylation inhibitors are highly sought. An integrated bioinformatics and mass spectrometry-based glycomics-driven glycoproteomics analysis pipeline was performed to identify an N-glycan inhibitor against lung cancer cells. Combined network pharmacology and in silico screening approaches were used to identify a potential inhibitor, pictilisib, against several glycosylation-related proteins, such as Alpha1-6FucT, GlcNAcT-V, and Alpha2,6-ST-I. A glycomics assay of lung cancer cells treated with pictilisib showed a significant reduction in the fucosylation and sialylation of N-glycans, with an increase in high mannose-type glycans. Proteomics analysis and in vitro assays also showed significant upregulation of the proteins involved in apoptosis and cell adhesion, and the downregulation of proteins involved in cell cycle regulation, mRNA processing, and protein translation. Site-specific glycoproteomics analysis further showed that glycoproteins with reduced fucosylation and sialylation were involved in apoptosis, cell adhesion, DNA damage repair, and chemical response processes. To determine how the alterations in N-glycosylation impact glycoprotein dynamics, modeling of changes in glycan interactions of the ITGA5–ITGB1 (Integrin alpha 5-Integrin beta-1) complex revealed specific glycosites at the interface of these proteins that, when highly fucosylated and sialylated, such as in untreated A549 cells, form greater hydrogen bonding interactions compared to the high mannose-types in pictilisib-treated A549 cells. This study highlights the use of mass spectrometry to identify a potential glycosylation inhibitor and assessment of its impact on cell surface glycoprotein abundance and protein–protein interaction.

Development of Low-Molecular-Weight Compounds Targeting the Cancer-Associated KLF5 Transcription Factor.

Krüppel-like factor 5 (KLF5) is a potential target for anticancer drugs. However, as an intrinsically disordered protein (IDP) whose tertiary structure cannot be solved, innovative strategies are needed. We focused on its hydrophobic α-helix structure, defined as an induced helical motif (IHM), which is a possible interface for protein-protein interaction. Using mathematical analyses predicting the α-helix's structure and hydrophobicity, a 4-amino-acid site (V-A-I-F) was identified as an IHM. Low-molecular-weight compounds that mimic the main chain conformation of the α-helix with the four side chains of V-A-I-F were synthesized using bicyclic pyrazinooxadiazine-4,7-dione. These compounds selectively suppressed the proliferation and survival of cancer cells but not noncancer cells and decreased the protein but not mRNA levels of KLF5 in addition to reducing proteins of Wnt signaling. The compounds further suppressed transplanted colorectal cancer cells in vivo without side effects. Our approach appears promising for developing drugs against key IDPs.

Design, Synthesis, Biological Evaluation, and Molecular Modeling of 2-Difluoromethylbenzimidazole Derivatives as Potential PI3Kα Inhibitors.

PI3Kα is one of the potential targets for novel anticancer drugs. In this study, a series of 2-difluoromethylbenzimidazole derivatives were studied based on the combination of molecular modeling techniques 3D-QSAR, molecular docking, and molecular dynamics. The results showed that the best comparative molecular field analysis (CoMFA) model had q2 = 0.797 and r2 = 0.996 and the best comparative molecular similarity indices analysis (CoMSIA) model had q2 = 0.567 and r2 = 0.960. It was indicated that these 3D-QSAR models have good verification and excellent prediction capabilities. The binding mode of the compound 29 and 4YKN was explored using molecular docking and a molecular dynamics simulation. Ultimately, five new PI3Kα inhibitors were designed and screened by these models. Then, two of them (86, 87) were selected to be synthesized and biologically evaluated, with a satisfying result (22.8 nM for 86 and 33.6 nM for 87).

Synthesis of Substituted Aryl Incorporated Oxazolo[4,5-b]Pyridine-Triazole Derivatives: Anticancer Evaluation and Molecular Docking Studies

A new series of structurally modified oxazolo[4,5-b]pyridine based triazoles (18a–j) derivatives were synthesized, and designed and screened for their anticancer activities against human cancer cell lines like PC3 (prostate), A549 (lung), MCF-7 (breast), and DU-145 (prostate) by using MTT assay method. Most of the tested compounds exhibited good to moderate anticancer potential in comparison with etoposide. Among all, compounds 18a, 18b, 18c, 18d, 18e, and 18i displayed promising anticancer activities on four cell lines. Furthermore, molecular docking studies were carried out on human dihydroorotate dehydrogenase (hDHODH), a potential target for anticancer drugs, that is linked to proliferation, invasion, and migration of cancerous cell in acute myeloid leukemia, colorectal cancer melanoma, and pancreatic cancer cells. The investigated oxazolo[4,5-b]pyridine-based triazoles (18a–j) showed efficient inhibition of hDHODH in molecular docking studies.

Discovery and Development of a Potent, Selective, and Orally Bioavailable CHK1 Inhibitor Candidate: 5-((4-((3-Amino-3-methylbutyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)picolinonitrile.

Checkpoint kinase 1 (CHK1) plays an important role in the DNA damage response pathway, being a potential anti-cancer drug target. In this study, we used a strategy for trifluoromethyl substitution to obtain orally bioavailable CHK1 inhibitors to overcome the limitations of lead compound 1, which can only be administered intravenously. After detailed investigation, we identified compound 6c as an oral CHK1 inhibitor, which demonstrated a considerably higher plasma exposure in mice. Compound 6c also showed good kinase selectivity. Moreover, it exhibited a significant antiproliferative effect in MV-4-11 cells singly and a synergistic effect in combination with gemcitabine in HT-29, A549, and RPMI-8226 cells. Additionally, compound 6c could inhibit tumor growth in the MV-4-11 xenograft mouse model. The combination of 6c and gemcitabine exhibited synergistic effect in the HT-29 xenograft mouse model. Thus, compound 6c was found to be a selective and oral potential anticancer CHK1 inhibitor.

Simple and Fast DNA Based Sensor System for Screening of Small-Molecule Compounds Targeting Eukaryotic Topoisomerase 1.

Background: Eukaryotic topoisomerase 1 is a potential target of anti-parasitic and anti-cancer drugs. Parasites require topoisomerase 1 activity for survival and, consequently, compounds that inhibit topoisomerase 1 activity may be of interest. All effective topoisomerase 1 drugs with anti-cancer activity act by inhibiting the ligation reaction of the enzyme. Screening for topoisomerase 1 targeting drugs, therefore, should involve the possibility of dissecting which step of topoisomerase 1 activity is affected. Methods: Here we present a novel DNA-based assay that allows for screening of the effect of small-molecule compounds targeting the binding/cleavage or the ligation steps of topoisomerase 1 catalysis. This novel assay is based on the detection of a rolling circle amplification product generated from a DNA circle resulting from topoisomerase 1 activity. Results: We show that the binding/cleavage and ligation reactions of topoisomerase 1 can be investigated separately in the presented assay termed REEAD (C|L) and demonstrate that the assay can be used to investigate, which of the individual steps of topoisomerase 1 catalysis are affected by small-molecule compounds. The assay is gel-free and the results can be detected by a simple colorimetric readout method using silver-on-gold precipitation rendering large equipment unnecessary. Conclusion: REEAD (C|L) allows for easy and quantitative investigations of topoisomerase 1 targeting compounds and can be performed in non-specialized laboratories.

Exploring novel capping framework: high substituent pyridine-hydroxamic acid derivatives as potential antiproliferative agents.

Histone deacetylases (HDACs) play a vital role in the epigenetic regulation of gene expression due to their overexpression in several cancer forms. Therefore, these enzymes are considered as a potential anticancer drug target. Different synthetic and natural structures have been studied as HDACs inhibitors; based on available structural design information, the capping group is important for the biological activity due to the different interactions in the active site entrance. The present study aimed to analyze high substituted pyridine as a capping group, which included carrying out the synthesis, antiproliferative activity analysis, and docking studies of these novel compounds. To achieve the synthesis of these derivatives, four reaction steps were performed, generating desired products 15a-k. Their effects on cell proliferation and gene expression of p21, cyclin D1, and p53 were determined using the sulphorhodamine B (SRB) method and quantitative real-time polymerase chain reaction. The HDAC1, HDAC6, and HDAC8 isoforms were used for performing docking experiments with our 15a-k products. The products 15a-k were obtained in overall yields of 40-71%. Compounds 15j and 15k showed the highest antiproliferative activity in the breast (BT-474 and MDA-MB-231) and prostate (PC3) cancer cell lines at a concentration of 10µM. These compounds increased p21 mRNA levels and decreased cyclin D1 and p53 gene expression. The docking study showed an increment in the strength, and in the number of interactions performed by the capping moiety of the tested molecules compared with SAHA; interactions displayed are mainly van der Waals, π-stacking, and hydrogen bond. The synthesized compounds 2-thiophene (15j) and 2-furan (15k) pyridine displayed cell growth inhibition, regulation of genes related to cell cycle progression in highly metastatic cancer cell lines. The molecular coupling analysis performed with HDAC1, HDAC6 and HDAC8 showed an increment in the number of interactions performed by the capping moiety and consequently in the strength of the capping group interaction.

Synthesis and biological activity of siRNA and Etoposide with magnetic nanoparticles on drug resistance model MCF-7 Cells: Molecular docking study with MRP1 enzyme

Objective(s): In this work, MRP-1 (Multidrug resistance-associated protein 1) gene expression levels and anticancer activity of siRNA and Etoposide loaded Poly-hydroxybutyrate (PHB) coated magnetic nanoparticles (MNPs) was studied on MCF-7/Sensitive and MCF-7/1000Etoposide resistance cells. For this purpose, PHB covered iron oxide-based magnetic nanoparticles (PHB-MNPs) were prepared by coprecipitation. We used magnetic nanoparticles because they include highly targeted to tumors in vivo cancer therapy. Materials and Methods: Etoposide, anti-cancer drug, was loaded onto the PHB-MNPs. The in vitro cytotoxicity analysis of siRNA and Etoposide-loaded PHB-MNPs was applied on cancer cells. The expression levels of MRP1 related to drug resistance were shown using qRT-PCR. In the present study, we also investigated whether nanoparticle system could be a potential anticancer drug target with molecular docking analyses.Results: The IC50 values of Etoposide on MCF-7/sensitive and MCF-7/1000Eto resistance cells were identified as 50,6 μM and 135,7 μM, respectively. IC50 values of siRNA and Etoposide loaded PHB coated magnetic nanoparticles were determined as 10,18 μM and 39,21 μM on MCF-7 and MCF-7/1000 Eto cells, respectively. According to the gene expression results, MRP1 expression was 4 fold upregulated in MCF-7/1000Eto cells. However, it was about 3 fold downregulated due to the application of siRNA-Etoposide loaded magnetic nanoparticles. Conclusion: According to the docking results, nanoparticle system may be a drug active substance with obtained results. The results of this study demonstrated that siRNA and Etoposide loaded PHB covered iron oxide based magnetic nanoparticles can be a potential targeted therapeutic agent to overcome drug resistance.

Molecular encapsulation of berberine and ethidium bromide in anthraquinonecarboxamido-β-cyclodextrin conjugate: supramolecular association with DNA duplex and G-quadruplexes

G-quadruplex DNA in recognized as a potential target for anti-cancer drugs. In this work, an anthraquinonecarboxamido derivative of β-cyclodextrin (AQCC) is synthesized as a novel DNA binder that further can deliver an additional molecule at the target, carrying it in the cavity of modified cyclodextrin. The binding of AQCC with ethidium bromide (EtBr), berberine (Ber), duplex calf-thymus DNA (CT-DNA), quadruplexes (G4) viz., kit22, myc22, and telo24 are studied. The compound acts as a host molecule for the encapsulation of DNA binders viz., EtBr, Ber and enhances their fluorescence due to the encapsulation in its AQCC’s cyclodextrin cavity. The binding constant of the host: guest complex of EtBr and Ber with AQCC’s cavity are 6.4 × 105 and 3.3 × 106 mol−1 dm3, respectively. The proximity of the protons of the guest and host molecules is confirmed by two-dimensional rotating-frame Overhauser effect spectroscopy (2D ROESY). The conjugate displays a quenching of fluorescence selectively on the association with CT-DNA and quadruplex kit22 that is contrast to the spectral behavior with quadruplex myc22 and telo24. CT-DNA exhibits dissimilar fluorescence spectra in free- and EtBr-bound forms. In addition, kit22 exhibit dissimilar emission profile when AQCC encapsulates Ber. Therefore, the Ber-loaded complexes and the AQCC molecule bind to different G-quadruplexes with different binding strengths. In addition, the effect of Ber in binding to the target DNAs is pronounces since the Ber molecule has more affinity to bind to quadruplexes than the duplex.

Transcriptional regulation of telomeric repeat-containing RNA by acridine derivatives

ABSTRACT Telomere is a specialized DNA–protein complex that plays an important role in maintaining chromosomal integrity. Shelterin is a protein complex formed by six different proteins, with telomeric repeat factors 1 (TRF1) and 2 (TRF2) binding to double-strand telomeric DNA. Telomeric DNA consists of complementary G-rich and C-rich repeats, which could form G-quadruplex and intercalated motif (i-motif), respectively, during cell cycle. Its G-rich transcription product, telomeric repeat-containing RNA (TERRA), is essential for telomere stability and heterochromatin formation. After extensive screening, we found that acridine derivative 2c and acridine dimer DI26 could selectively interact with TRF1 and telomeric i-motif, respectively. Compound 2c blocked the binding of TRF1 with telomeric duplex DNA, resulting in up-regulation of TERRA. Accumulated TERRA could bind with TRF1 at its allosteric site and further destabilize its binding with telomeric DNA. In contrast, DI26 could destabilize telomeric i-motif, resulting in down-regulation of TERRA. Both compounds exhibited anti-tumour activity for A549 cells, but induced different DNA damage pathways. Compound 2c significantly suppressed tumour growth in A549 xenograft mouse model. The function of telomeric i-motif structure was first studied with a selective binding ligand, which could play an important role in regulating TERRA transcription. Our results showed that appropriate level of TERRA transcript could be important for stability of telomere, and acridine derivatives could be further developed as anti-cancer agents targeting telomere. This research increased understanding for biological roles of telomeric i-motif, TRF1 and TERRA, as potential anti-cancer drug targets.

Discovery of 6-(7-Nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol Derivatives as Glutathione Transferase Inhibitors with Favorable Selectivity and Tolerated Toxicity.

Glutathione transferase (GST P1-1) is a potential target for anticancer drugs. In this work, a series of 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol (NBDHEX) derivatives as GST P1-1 inhibitors were designed, synthesized, and evaluated for their biological activity. Among the target compounds, 4n showed more selective inhibition toward GST P1-1 and GST M2-2, better water solubility, and more potent anticancer activities toward all the tested cancer cells (except for HOS) than its parent molecule. Detailed biological studies on the effect of 4n toward 143b cells revealed that 4n could arrest the cell cycle at the G2 phase and induced cell apoptosis in a dose-dependent manner. Like NBDHEX, 4n displayed good pharmacokinetic characteristics. An in vivo study on 143b xenograft models demonstrated that 4n could significantly reduce tumor growth in a dose-dependent manner, showing stronger antitumor activity than NBDHEX. Thus, 4n deserves to be further investigated as a potential antitumor agent for cancer therapy.

Structural insights into vesicle amine transport-1 (VAT-1) as a member of the NADPH-dependent quinone oxidoreductase family

Vesicle amine transport protein-1 (VAT-1) has been implicated in the regulation of vesicular transport, mitochondrial fusion, phospholipid transport and cell migration, and is a potential target of anticancer drugs. Little is known about the molecular function of VAT-1. The amino acid sequence indicates that VAT-1 belongs to the quinone oxidoreductase subfamily, suggesting that VAT-1 may possess enzymatic activity in unknown redox processes. To clarify the molecular function of VAT-1, we determined the three-dimensional structure of human VAT-1 in the free state at 2.3 Å resolution and found that VAT-1 forms a dimer with the conserved NADPH-binding cleft on each protomer. We also determined the structure of VAT-1 in the NADP-bound state at 2.6 Å resolution and found that NADP binds the binding cleft to create a putative active site with the nicotine ring. Substrate screening suggested that VAT-1 possesses oxidoreductase activity against quinones such as 1,2-naphthoquinone and 9,10-phenanthrenequinone.

KRAS Promoter G-Quadruplexes from Sequences of Different Length: A Physicochemical Study.

DNA G-quadruplexes (G4s) form in relevant genomic regions and intervene in several biological processes, including the modulation of oncogenes expression, and are potential anticancer drug targets. The human KRAS proto-oncogene promoter region contains guanine-rich sequences able to fold into G4 structures. Here, by using circular dichroism and differential scanning calorimetry as complementary physicochemical methodologies, we compared the thermodynamic stability of the G4s formed by a shorter and a longer version of the KRAS promoter sequence, namely 5′-AGGGCGGTGTGGGAATAGGGAA-3′ (KRAS 22RT) and 5′-AGGGCGGTGTGGGAAGAGGGAAGAGGGGGAGG-3′ (KRAS 32R). Our results show that the unfolding mechanism of KRAS 32R is more complex than that of KRAS 22RT. The different thermodynamic stability is discussed based on the recently determined NMR structures. The binding properties of TMPyP4 and BRACO-19, two well-known G4-targeting anticancer compounds, to the KRAS G4s were also investigated. The present physicochemical study aims to help in choosing the best G4 target for potential anticancer drugs.

Mapping Synthetic Dosage Lethal Genetic Interactions in Saccharomyces cerevisiae.

Synthetic dosage lethality (SDL) is a type of genetic interaction that occurs when increasing the expression of a gene causes a fitness defect, such as lethality, in a specific mutant background but has little effect on fitness in a wild-type background. SDL genetic interactions discovered in model organisms such as the budding yeast, Saccharomyces cerevisiae , represent candidate genetic interactions that may be conserved in human cells. In some cases, SDL genetic interactions can be applied to study the biological implications of genes overexpressed in cancer and to discover potential anticancer therapeutic drug targets. Here, we provide a protocol for screening a query overexpression gene against ordered arrays of yeast mutant strains to identify mutations that sensitize yeast to increased dosage of a specific gene product. We outline applications and procedures for screening with an inducibly overexpressed wild-type gene, a common feature of cancer cells, or with an inducibly overexpressed gene carrying a dominant-negative missense mutation as a model of protein-inhibitor interactions. This high-throughput screening platform is adapted from synthetic genetic array (SGA) technology and enables the generation of large-scale SDL genetic interaction networks that can be applied to study gene/pathway function and to identify cross-species cancer-relevant processes.

Synthesis, structures and anticancer potentials of five platinum(II) complexes with benzothiazole-benzopyran targeting mitochondria

Mitochondria were potential therapeutic targets for Pt-based anticancer drugs. Thus, five mitochondrion-targeted novel Pt(II) complexes, [Pt(FB1)Cl2] (FB1-Pt), [Pt(OHB)Cl2] (OHB-Pt), [Pt(FB2)Cl2] (FB2-Pt), [Pt(MB)Cl2]⋅CH3OH (MB-Pt) and [Pt(ClB)Cl2] (ClB-Pt) containing 3-(benzo[d]thiazol-2-yl)-8-fluoro-2H-chromen-2-imine (FB1), 3-(benzo[d]thiazol-2-yl)-2-imino-2H-chromen-8-ol (OHB), 3-(benzo[d]thiazol-2-yl)-7-fluoro-2H-chromen-2-imine (FB2), 3-(benzo[d]thiazol-2-yl)-N,N-diethyl-2-imino-2H-chromen-7-amine (MB) and 3-(benzo[d]thiazol-2-yl)-6-chloro-2H-chromen-2-imine (ClB), has been synthesized and characterized by single-crystal X-ray diffraction and elemental analysis. All of them benzothiazole-benzopyran Pt(II) derivatives were more cytotoxic to the cisplatin-resistant A549/DDP cells, with complex FB1-Pt displaying 525.5-fold higher activity than cisplatin, which should be certainly correlated with the key roles of different substituted groups in the benzothiazole-benzopyran derivatives. Strikingly, complex FB1-Pt, featuring 8-fluoro-benzothiazole-benzopyran, was the most efficacious, with nanomole IC50 concentrations. Interestingly, the benzothiazole-benzopyran Pt(II) derivatives displayed low toxicity against normal HL-7702 cells. Cellular distribution studies suggested that FB1-Pt accumulate more preferentially in mitochondria than in nuclei fraction. As a result, FB1-Pt causes a remarkable decrease in the membrane of mitochondria in the A549/DDP cancer cells, leading to more radical mitochondrial dysfunctions than that of OHB-Pt. The results indicated that mitochondrion-targeted benzothiazole-benzopyran Pt(II) derivatives may have potential to overcome the drug resistance of traditional cisplatin-based antitumor drugs.

Over expression of PTEN induces apoptosis and prevents cell proliferation in breast cancer cells.

The phosphatase and tensin homolog (PTEN) is a tumor suppressor lipid phosphatase frequently mutated or deleted in breast cancer cells. Loss of PTEN is associated with aberrant activation of P13K/AKT signaling pathways, which are responsible for uncontrolled cell cycle, migration and prolonged survival. Therefore, stability and functional PTEN is essential for prevention of cancer growth and migration. In the present study, we have determined the effect of PTEN over expression in apoptosis induction and cell proliferation in breast cancer cells. We showed that PTEN over expression significantly declined the cell proliferation rate during logarithmic growth phase. Furthermore, the PTEN over expression leads to the activation of mitochondrial based intrinsic apoptosis pathways, which is confirmed by the activation and over expression of caspases 9 and caspases 3. In addition, the number of apoptotic cells are significantly more in PTEN over expressed cells, where they showed more apoptotic bodies in AO-EtBr and Hoechst 33344 staining. Finally, PTEN over expressed cells showed decreased chemo resistance as chemotherapeutic drugs kill them efficiently. Therefore, our findings suggest that tumor suppressive effect of PTEN is crucial for cancer prevention and thus PTEN might be a potential target for anti-cancer drugs.