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Fulltext Understanding Apoptosis and Apoptotic Pathways Targeted Cancer Therapeutics

Jan R, Chaudhry GE

Adv Pharm Bull, 2019 Jun;9(2):205-218.
PMID: 31380246 DOI: 10.15171/apb.2019.024

Various physiological processes involve appropriate tissue developmental process and homeostasis - the pathogenesis of several diseases connected with deregulatory apoptosis process. Apoptosis plays a crucial role in maintaining a balance between cell death and division, evasion of apoptosis results in the uncontrolled multiplication of cells leading to different diseases such as cancer. Currently, the development of apoptosis targeting anticancer drugs has gained much interest since cell death induced by apoptosis causes minimal inflammation. The understanding of complexities of apoptosis mechanism and how apoptosis is evolved by tumor cells to oppose cell death has focused research into the new strategies designed to induce apoptosis in cancer cells. This review focused on the underlying mechanism of apoptosis and the dysregulation of apoptosis modulators involved in the extrinsic and intrinsic apoptotic pathway, which include death receptors (DRs) proteins, cellular FLICE inhibitory proteins (c-FLIP), anti-apoptotic Bcl-2 proteins, inhibitors of apoptosis proteins (IAPs), tumor suppressor (p53) in cancer cells along with various current clinical approaches aimed to selectively induce apoptosis in cancer cells.
Antibacterial evaluation of silver nanoparticles synthesized from lychee peel: individual versus antibiotic conjugated effects

Perveen S, Safdar N, Chaudhry GE, Yasmin A

World J Microbiol Biotechnol, 2018 Jul 14;34(8):118.
PMID: 30008019 DOI: 10.1007/s11274-018-2500-1

This paper describes the extracellular synthesis of silver nanoparticles from waste part of lychee fruit (peel) and their conjugation with selected antibiotics (amoxicillin, cefixim, and streptomycin). FTIR studies revealed the reduction of metallic silver and stabilization of silver nanoparticles and their conjugates due to the presence of CO (carboxyl), OH (hydroxyl) and CH (alkanes) groups. The size of conjugated nanoparticles varied ranging from 3 to 10 nm as shown by XRD. TEM image revealed the spherical shape of biosynthesized silver nanoparticles. Conjugates of amoxicillin and cefixim showed highest antibacterial activity (147.43 and 107.95%, respectively) against Gram-negative bacteria i.e. Alcaligenes faecalis in comparison with their control counterparts. The highest reduction in MIC was noted against Gram-positive strains i.e. Enterococcus faecium (75%) and Microbacterium oxydans (75%) for amoxicillin conjugates. Anova two factor followed by two-tailed t test showed non-significant results both in case of cell leakage and protein estimation between nanoparticles and conjugates of amoxicillin, cefixime and streptomycin. In case of MDA release, non-significant difference among the test samples against the selected strains. Our study found green-synthesized silver nanoparticles as effective antibacterial bullet against both Gram positive and Gram negative bacteria, but they showed a more promising effect on conjugation with selected antibiotics against Gram negative type.
Fulltext Vitex rotundifolia fractions induce apoptosis in human breast cancer cell line, MCF-7, via extrinsic and intrinsic pathways

Chaudhry GE, Jan R, Mohamad H, Tengku Muhammad TS

Res Pharm Sci, 2019 Jun;14(3):273-285.
PMID: 31160905 DOI: 10.4103/1735-5362.258496

Breast cancer is amongst frequently diagnosed cancer type throughout the world. Due to reduced efficacy of current chemotherapeutics, several natural products have been screened for better alternatives. The cytotoxic activity of fractions prepared from leaves extract of Vitex rotundifolia (V. rotundifolia) on human breast cancer cell line, MCF-7 was studied. The fractions F1, F2, F3, and F5 of V. rotundifolia produced concentration-dependent cytotoxic effects on MCF-7 cell line. The relative potential of cytotoxicity of the fractions on MCF-7 cell line was found to be F3 > F2 > F5 > F1. The active fractions induce apoptosis in MCF-7 cell line determined by annexin V base assay. The phosphatidylserine externalization and the presence of DNA fragmentation in treated cells confirms the early and late apoptosis in treated cells. The V. rotundifolia fractions induced apoptosis by both pathways; extrinsic pathways via activation of caspase-8 and intrinsic pathways through enhanced bax/bcl-2 ratio and activation of caspase-3/7 and caspase-9 proapoptotic proteins. Furthermore, chemical profiling indicates various phenolic, flavonoids, and terpenoids compounds in the active fractions. Thus, V. rotundifolia might be a suitable candidate to investigate further and develop molecular targeted cancer therapeutics by understanding the fundamental mechanisms involved in the regulation of cell death in cancer cells.
Hispidulin: a promising anticancer agent and mechanistic breakthrough for targeted cancer therapy

Chaudhry GE, Zeenia, Sharifi-Rad J, Calina D

Naunyn Schmiedebergs Arch Pharmacol, 2024 Apr;397(4):1919-1934.
PMID: 37594522 DOI: 10.1007/s00210-023-02645-9

Cancer is a complex disease characterized by dysregulated cell growth and division, posing significant challenges for effective treatment. Hispidulin, a flavonoid compound, has shown promising biological effects, particularly in the field of anticancer research. The main objective of this study is to investigate the anticancer properties of hispidulin and gain insight into its mechanistic targets in cancer cells. A comprehensive literature review was conducted to collect data on the anticancer effects of hispidulin. In vitro and in vivo studies were analyzed to identify the molecular targets and underlying mechanisms through which hispidulin exerts its anticancer activities. Hispidulin has shown significant effects on various aspects of cancer, including cell growth, proliferation, cell cycle regulation, angiogenesis, metastasis, and apoptosis. It has been observed to target both extrinsic and intrinsic apoptotic pathways, regulate cell cycle arrest, and modulate cancer progression pathways. The existing literature highlights the potential of hispidulin as a potent anticancer agent. Hispidulin exhibits promising potential as a therapeutic agent for cancer treatment. Its ability to induce apoptosis and modulate key molecular targets involved in cancer progression makes it a valuable candidate for further investigation. Additional pharmacological studies are needed to fully understand the specific targets and signaling pathways influenced by hispidulin in different types of cancer. Further research will contribute to the successful translation of hispidulin into clinical settings, allowing its utilization in conventional and advanced cancer therapies with improved therapeutic outcomes and reduced side effects.
Fulltext Induction of apoptosis and role of paclitaxel-loaded hyaluronic acid-crosslinked nanoparticles in the regulation of AKT and RhoA

Chaudhry GE, Akim A, Zafar MN, Abdullah MA, Sung YY, Muhammad TST

J Adv Pharm Technol Res, 2020 07 14;11(3):101-106.
PMID: 33102192 DOI: 10.4103/japtr.JAPTR_26_20

Cancer is a complex multifactorial disease and leading causes of death worldwide. Despite the development of many anticancer drugs, there is a reduced survival rate due to severe side effects. The nontargeted approach of convention drugs is one of the leading players in context to toxicity. Hyaluronan is a versatile bio-polymer and ligand of the receptor (CD44) on cancer cells. The MCF-7 and HT-29 cancer cell lines treated with hyaluronic acid-paclitaxel (HA-PTX) showed the distinguishing morphological features of apoptosis. Flow cytometric analysis showed that HA-PTX induces apoptosis as a significant mode of cell death. The activation level of tumor suppressor protein (p53) increased after PTX treatment in MCF-7, but no changes observed in HT-29 might be due to hereditary mutations. The lack of suppression in AKT and Rho A protein suggest the use of possible inhibitors in future studies which might could play a role in increasing the sensitivity of drug towards mutated cells line and reducing the possibilities for cancer cell survival, migration, and metastasis.
Fulltext Understanding Hyaluronan Receptor (CD44) Interaction, HA-CD44 Activated Potential Targets in Cancer Therapeutics

Chaudhry GE, Akim A, Naveed Zafar M, Safdar N, Sung YY, Muhammad TST

Adv Pharm Bull, 2021 May;11(3):426-438.
PMID: 34513617 DOI: 10.34172/apb.2021.050

Cancer is a complex mechanism involving a series of cellular events. The glycoproteins such as hyaluronan (HA) are a significant element of extracellular matrix (ECM), involve in the onset of cancer developmental process. The pivotal roles of HA in cancer progression depend on dysregulated expression in various cancer. HA, also gain attention due to consideration as a primary ligand of CD44 receptor. The CD44, complex transmembrane receptor protein, due to alternative splicing in the transcription process, various CD44 isoforms predominantly exist. The overexpression of distinct CD44 isoforms (CD44v) standard (CD44s) depends on the tumour type and stage. The receptor proteins, CD44 engage in a variety of biological processes, including cell growth, apoptosis, migration, and angiogenesis. HA-CD44 interaction trigger survival pathways that result in cell proliferation, invasion ultimately complex metastasis. The interaction and binding of ligand-receptor HA-CD44 regulate the downstream cytoskeleton pathways involve in cell survival or cell death. Thus, targeting HA, CD44 (variant and standard) isoform, and HA-CD44 binding consider as an attractive and useful approach towards cancer therapeutics. The use of various inhibitors of HA, hyaluronidases (HYALs), and utilizing targeted Nano-delivery of anticancer agents and antibodies against CD44, peptides gives promising results in vitro and in vivo. However, they are in clinical trials with favourable and unfavourable outcomes, which reflects the need for various modifications in targeting agents and a better understanding of potential targets in tumour progression pathways.
Targeted drug delivery systems: synthesis and in vitro bioactivity and apoptosis studies of gemcitabine-carbon dot conjugates

Yunus U, Zulfiqar MA, Ajmal M, Bhatti MH, Chaudhry GE, Muhammad TST, et al.

Biomed Mater, 2020 09 26;15(6):065004.
PMID: 32442994 DOI: 10.1088/1748-605X/ab95e1

Gemcitabine (GEM) is used to treat various cancers such as breast, pancreatic, non-small lung, ovarian, bladder, and cervical cancers. GEM, however, has the problem of non-selectivity. Water-soluble, fluorescent, and mono-dispersed carbon dots (CDs) were fabricated by ultrasonication of sucrose. The CDs were further conjugated with GEM through amide linkage. The physical and morphological properties of these carbon dot-gemcitabine (CD-GEM) conjugates were determined using different analytical techniques. In vitro cytotoxicity and apoptosis studies of CD-GEM conjugates were evaluated by various bioactivity assays on human cell lines, MCF-7 (human breast adenocarcinoma), and HeLa (cervical cancer) cell lines. The results of kinetic studies have shown a maximum drug loading efficacy of 17.0 mg of GEM per 50.0 mg of CDs. The CDs were found biocompatible, and the CD-GEM conjugates exhibited excellent bioactivity and exerted potent cytotoxicity against tumor cells with an IC50 value of 19.50 μg ml-1 in HeLa cells, which is lower than the IC50 value of pure GEM (∼20.10 μg ml-1). In vitro studies on CD-GEM conjugates demonstrated the potential to replace the conventional administration of GEM. CD-GEM conjugates are more stable, have a higher aqueous solubility, and are more cytotoxic as compared to GEM alone. The CD-GEM conjugates show reduced side effects in the normal cells along with excellent cellular uptake. Hence, CD-GEM conjugates are more selective toward cancerous cell lines as compared to non-cancerous cells. Also, the CD-GEM conjugates successfully induced early and late apoptosis in cancer cell lines and might be effective and safe to use for in vivo applications.
Fulltext Vitex Rotundifolia Fractions Induced Apoptosis in Human Breast Cancer T-47D Cell Line via Activation of Extrinsic and Intrinsic Pathway

Chaudhry GE, Jan R, Naveed Zafar M, Mohammad H, Muhammad TST

Asian Pac J Cancer Prev, 2019 Dec 01;20(12):3555-3562.
PMID: 31870094 DOI: 10.31557/APJCP.2019.20.12.3555

OBJECTIVE: Breast cancer is the most frequently diagnosed cancer worldwide. The main objective of the present study was to evaluate the cytotoxic effects and mechanism of cell death induced by the extract and fractions of Vitex rotundifolia (leaves) in breast cancer cell line, T-47D.
METHODS: The cytotoxicity activity was measured using MTS assay. The mode of cell death was analysed by early (phosphatidylserine externalization) and late apoptosis (DNA fragmentation). The caspases 8, 9, 3/7 and apoptotic proteins bax, bcl-2 study were done by western blot and ELISA method.
RESULTS: The methanol extract was found to inhibit 50% growth of T-47D cells at the concentration of 79.43µg/ml respectively after 72hr. From seven fractions, fraction F1, F2 and F3 produced cytotoxicity effects in T-47D cell line with IC50 (72hr) < 30µg/ml. The results obtained by Annexin V/PI apoptosis detection assay and TUNEL assay suggest that active fractions of Vitex rotundifolia induced early and late apoptosis (DNA fragmentation) in T-47D cell line. Moreover, western blot analysis and Caspase GloTM luminescent assay demonstrated that fractions F2 and F3 triggered apoptotic cell death via activation of caspases -8, -9 and -3/7 and up-regulation of Bax and down-regulation of Bcl-2 protein. Furthermore, chemical profiling confirms the presence of potential metabolites (vitexicarpin) in fractions of Vitex rotundifolia.
CONCLUSION: Thus, the present study suggests the remarkable potential of active metabolites in fractions of Vitex rotundifolia as future cancer therapeutic agent for the treatment of breast cancer.
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Development of biodegradable thin films for efficient, specific and controlled delivery of capecitabine

Gul I, Yunus U, Ajmal M, Bhatti MH, Chaudhry GE

Biomed Mater, 2021 Aug 31;16(5).
PMID: 34375958 DOI: 10.1088/1748-605X/ac1c61

Cancer is the leading cause of death worldwide. Capecitabine (CP) shows severe side effects because of early metabolism in stomach that affects the normal cells and organs, particularly liver and stomach. In this scope, we report the biocompatible, nontoxic polymeric thin films loaded with anti-cancer drug, CP for target specific, sublingual delivery of CP. Chitosan (CS) and polyvinyl alcohol (PVA) were used as biodegradable polymers alongwith glutaraldehyde (GLA) cross linker. CP-loaded thin films (TFCP1-TFCP5) were fabricated by solvent casting method. The results of Fourier transform infrared spectroscopy confirmed the presence of CP and polymers (CS and PVA) with GLA which binds through hydrogen bonding, and compatibility of drug with different excipients. Thermogravemetric analysis showed that the thin films are highly stable while differential scanning calorimeter thermograms confirmed the complete miscibility/entrapment of CP within PVA/CS thin film matrix. X-ray diffraction patterns revealed the molecular ineractions between CP and polymer matrix. High degree of swelling index of thin films at pH 7.4 was observed in comparison to pH 5.5. CP release studies in acetate (pH 5.5) and phosphate buffer (pH 7.4) showed that the thin films swell and result in drug diffusion faster in phosphate buffer through diffusion governed by Higuchi's model. Cytotoxicity results displayed that CPTFs killed MCF-7 and T47D (human breast adenocarcinoma) cells more effectively as compared to CP alone. The results of adhesion assay also showed that the PVA and CS both are safe and biocompatible. TFCP1 and TFCP3 thin films efficiently induced the apoptosis as compared to CP alone. The improved ability of TFCP1 and TFCP3 to induce cytotoxicity in MCF-7 cells reflects the potential of these thin films for targeted drug delivery. The CPTFs were stable for 4 months at 4 °C/60% ± 2%RH and 25 °C/70% ± 2%RH. In conclusion, the thin film formulations showed target specific controlled and burst release properties and thus could prove to be effective for human breast cancer treatment.
Fulltext Cancer and Disease Diagnosis - Biosensor as Potential Diagnostic Tool for Biomarker Detection

Chaudhry GE, Akim AM, Safdar N, Yasmin A, Begum S, Sung YY, et al.

J Adv Pharm Technol Res, 2022;13(4):243-247.
PMID: 36568055 DOI: 10.4103/japtr.japtr_106_22

Analysis of cancer biomarkers has enormous promise for advancing our molecular understanding of illness and facilitating more precise and timely diagnosis and follow-up care. MicroRNA, exosomes, ctDNA, CTCs, and proteins are only some of the circulating biomarkers that can be detected by liquid biopsy instead of the more intrusive and time-consuming process of doing a tissue biopsy. As the cancer diagnosis bio-markers reveal ultra-low levels in the early stages of the disease, highly sensitive approaches are urgently required. Researchers have taken an interest in a optical biosensor for detecting cancer biomarkers as a potential tool for early disease diagnosis. These techniques have the potential to aid in the development of effective treatments, ultimately leading to a higher rate of patient survival. This review briefly discuss the i) understanding of cancer and biomarkers for early diagonosis purpose ii) Molecular methods and ii) biosensor-based diagnostics. The reseach primary focus on advancement in biosensor design using various concepts ie., Electrochemical, Chemiluminescence and Colorimetric, Surface plasmons (SP), Surface plasmon resonance (SPR), localized surface plasmon resonance (LSPR), Fluorescence, Fiber-based sensors, Terahertz based biosensors, and Surface enhanced Raman spectroscopy (SERS). As a result of the local electric field amplification around plasmonic (usually gold and silver) nanostructures, surface-enhanced Raman spectroscopy (SERS) has emerged as a rapid, selective, and sensitive alternative to conventional laboratory analytical methods, making significant strides in a number of biosensing applications but still under developing stage to be used as diagnostic tool in clinical research.
Corrigendum: Targeted drug delivery systems: synthesis andin vitrobioactivity and apoptosis studies of gemcitabine-carbon dot conjugates (2020Biomed. Mater.15065004)

Yunus U, Zulfiqar MA, Ajmal M, Bhatti MH, Chaudhry GE, Muhammad TST, et al.

Biomed Mater, 2023 Sep 01;18(5).
PMID: 37665183 DOI: 10.1088/1748-605X/acf358
Corrigendum: Development of biodegradable thin films for efficient, specific, and controlled delivery of capecitabine (2021Biomed. Mater.16 055019)

Gul I, Yunus U, Ajmal M, Bhatti MH, Chaudhry GE

Biomed Mater, 2023 Jul 21;18(5).
PMID: 37476965 DOI: 10.1088/1748-605X/ace6e6
Fulltext Characterization and cytotoxicity of low-molecular-weight chitosan and chito-oligosaccharides derived from tilapia fish scales

Chaudhry GE, Thirukanthan CS, NurIslamiah KM, Sung YY, Sifzizul TSM, Effendy AWM

J Adv Pharm Technol Res, 2021;12(4):373-377.
PMID: 34820312 DOI: 10.4103/japtr.japtr_117_21

The present study evaluated the physicochemical characterization and cytotoxicity activity of chitosan and chito-oligosaccharides (COSs). The extraction of chitosan and COSs was executed by chemical hydrolysis. The physicochemical characterization and deacetylation (DA) value were determined using an FTIR. The molecular weight was determined by using the Mark-Houwink equation. The physical parameters such as solubility, water-binding capacity (WBC), and fat-binding capacity (FBC) were determination as per equation (i), (ii), and (iii) respectively. The cytotoxic activities of chitosan and COS against MCF-7, HepG2, HeLa-6, and 3T3 were performed by MTS assay. The COS induced enhance cytotoxicity with IC50 0.87 and2.21 mg/ml against MCF-7 and HepG2 respectively. However, COSs seem to be more sensitive toward the cell lines with the relative potential of MCF-7 > HepG2 > HeLa. Hence, the results showed promising future perspectives of chitosan and COS to develop biodegradable, antibacterial, cytotoxic naturally derived polysaccharides for cancer drug delivery and smart wound dressings.
Advancing Research on Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors: A Scientometric Analysis

Matin A, Chaudhry GE, Azra MN, Gazali M, Yeong YS, Tengku Muhammad TS

Malays J Med Sci, 2024 Aug;31(4):14-34.
PMID: 39247108 DOI: 10.21315/mjms2024.31.4.2

Atherosclerosis is characterised by the accumulation of fatty deposits and plaque as a result of a continuously high level of low-density lipoprotein cholesterol (LDL-C) in the blood. The primary objective of this research is to assess the current status of knowledge, research endeavours and developmental trajectories about proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors in correlation with atherosclerosis treatment. Additionally, this study aims to compile bibliometric and scientometric investigations within this domain through rigorous scientometric analysis. Analysing the bibliometric landscape and global research trends associated with PCSK9 inhibitors can contribute valuable insights into comprehending atherosclerosis. This is exemplified by examining publications within the Web of Science Core Collection (WOSCC) database from 2008 to 2022. Citespace was used for frequency, co-occurrence, co-citation, grouping and burst analysis, and Microsoft Excel was used to manage descriptive datasets. Eight hundred eighty-five publications available from WOSCC database between the years 2008 and 2022 were extracted and examined. Over the period, 3,138 collaborating institutions from 87 countries, a staggering 7,750 writers involved and 325 distinct journals published about PCSK9 inhibitors studies. Among authors, Sabatine et al. and the journal The New England Journal of Medicine has had the most significant impact. Lipid-lowering therapy and bempedoic acid are the most prominent topical clusters associated with PCSK9 inhibitors, and the most often used keywords are efficacy, safety and PCSK9 inhibitors. We believe this is the first comprehensive analysis of PCSK9 inhibitors research and publications conducted using Scientometric. These results demonstrate the nascence of PCSK9 inhibitors research. They may encourage a wide range of stakeholders, particularly early career researchers from various disciplines, to work together in the future.
Regression models for sediment transport in tropical rivers

Harun MA, Safari MJS, Gul E, Ab Ghani A

Environ Sci Pollut Res Int, 2021 Oct;28(38):53097-53115.
PMID: 34023993 DOI: 10.1007/s11356-021-14479-0

The investigation of sediment transport in tropical rivers is essential for planning effective integrated river basin management to predict the changes in rivers. The characteristics of rivers and sediment in the tropical region are different compared to those of the rivers in Europe and the USA, where the median sediment size tends to be much more refined. The origins of the rivers are mainly tropical forests. Due to the complexity of determining sediment transport, many sediment transport equations were recommended in the literature. However, the accuracy of the prediction results remains low, particularly for the tropical rivers. The majority of the existing equations were developed using multiple non-linear regression (MNLR). Machine learning has recently been the method of choice to increase model prediction accuracy in complex hydrological problems. Compared to the conventional MNLR method, machine learning algorithms have advanced and can produce a useful prediction model. In this research, three machine learning models, namely evolutionary polynomial regression (EPR), multi-gene genetic programming (MGGP) and M5 tree model (M5P), were implemented to model sediment transport for rivers in Malaysia. The formulated variables for the prediction model were originated from the revised equations reported in the relevant literature for Malaysian rivers. Among the three machine learning models, in terms of different statistical measurement criteria, EPR gives the best prediction model, followed by MGGP and M5P. Machine learning is excellent at improving the prediction distribution of high data values but lacks accuracy compared to observations of lower data values. These results indicate that further study needs to be done to improve the machine learning model's accuracy to predict sediment transport.
Fulltext Induction of cytotoxicity by Bruguiera gymnorrhiza in human breast carcinoma (MCF-7) cell line via activation of the intrinsic pathway

Chaudhry GE, Rahman NH, Sevakumaran V, Ahmad A, Mohamad H, Zafar MN, et al.

J Adv Pharm Technol Res, 2020 10 10;11(4):233-237.
PMID: 33425710 DOI: 10.4103/japtr.JAPTR_81_20

Breast cancer is among the frequently occurring cancer worldwide. The foremost underline aim of this study was to determine the growth inhibitory effect along with mechanistic study of a Bruguiera gymnorrhiza extract on MCF-7. The cytotoxicity activity was determined by using the MTS assay. Butanol extract exhibited the maximum cytotoxicity activity against the MCF-7 cells with IC50 of 3.39 μg/mL, followed by diethyl ether and methanol extract (IC50 at 16.22 μg/mL and 37.15 μg/mL, respectively) at 72 h. The DeadEndTM Colorimetric Apoptosis Detection System confirmed the induction of apoptosis (via DNA fragmentation) in MCF-7 cells. Both butanol and diethyl ether extracts of B. gymnorrhiza significantly increase the caspase-3 level. However, the diethyl ether extract induced higher caspase-9 levels compared to caspase-8, suggesting that the intrinsic pathway was the major route in the process of apoptosis. Thin-layer chromatography profiling demonstrated the presence of phenolic, terpene, and alkaloid compounds in crude methanol, diethyl ether, and butanol extracts. The phytochemicals present in the extracts of B. gymnorrhiza might have the potential to be a future therapeutic agent against breast cancer.
Synthesis, characterization and anti-cancer properties of water-soluble bis(PYE) pro-ligands and derived palladium(ii) complexes

Zafar MN, Masood S, Chaudhry GE, Muhammad TST, Dalebrook AF, Nazar MF, et al.

Dalton Trans, 2019 Aug 08.
PMID: 31393494 DOI: 10.1039/c9dt01923e

The two cationic palladium(ii) complexes, [Pd(Len)2][OTf]2 (4) and [Pd(Lphen)2][OTf]2 (5), were synthesized by treatment of bis(benzonitrile)dichloropalladium(ii) with [H2Len][OTf]2 (2) or [H2Lphen][OTf]2 (3), respectively, in the presence of a weak base. The pro-ligands 2 and 3 were synthesized by melt reactions between N-methyl-4-chloropyridinium triflate (1) and the amines ethylenediamine or phenylenediamine, respectively. The water-soluble compounds 2-5 were fully characterized, including by single-crystal X-ray crystal structure determinations for 2-4. UV-Vis and fluorescence spectroscopy were used to study the binding interactions of 2-5 with CT-DNA. The spectroscopic data suggested the presence of intercalative and groove binding modes and this was supported by molecular docking studies. The in vitro cytotoxicity studies (IC50 values) showed that the human breast cancer cell lines MCF-7 and T47D were more sensitive towards 3, 4 and 5 than cisplatin. The cytotoxicity of the new compounds decreased in the order 5 > 4 > 3 > 2. Furthermore, the annexin V-FITC staining method strongly suggested the presence of phosphatidylserine (PS) on the outer membrane of the treated cells, which is a hallmark of apoptosis.
Two new monofunctional platinum(II) dithiocarbamate complexes: phenanthriplatin-type axial protection, equatorial-axial conformational isomerism, and anticancer and DNA binding studies

Imran M, Rehman ZU, Hogarth G, Tocher DA, Chaudhry GE, Butler IS, et al.

Dalton Trans, 2020 Nov 10;49(43):15385-15396.
PMID: 33140800 DOI: 10.1039/d0dt03018j

The syntheses of two platinum(ii) dithiocarbamate complexes (1 and 2) that show quinoplatin- and phenanthriplatin-type axial protection of the Pt-plane are described. The Pt-plane of complex 2 is axially more protected than that of complex 1. Furthermore, both complexes adopt two different stereochemical conformations in the solid state (based on single-crystal X-ray structures) owing to the structurally flexible piperazine backbone; i.e., C-e,e-Anti (1) and C-e,a-Syn (2), where "C" stands for the chair configuration, "e" and "a" stand for the equatorial and axial positions and "Anti" (opposite side) and "Syn" (same side) represent the relative orientations in space of the terminal substituents on the piperazine ring. In complex 2, the C-e,a-Syn conformation may provide additional steric hindrance to the Pt-plane. Despite the lower lipophilicity of 2 as compared to that of 1, the in vitro anticancer action against selected cancer cell lines is better for the former revealing the superior role of the axial protection over lipophilicity in modulating anticancer activity. The activity against the cancer promoting protein NF-κB signifies that the mode of cancer cell death may be the result of hindering the activity of NF-κB in the initiation of apoptosis. The apoptotic mode of cell death has been established earlier in a study using Annexin V-FITC. Finally, DNA binding studies revealed that the complex-DNA adduct formation is spontaneous and the mode of interaction is non-intercalative (electrostatic/covalent).
Fulltext Xylocarpus Moluccensis Induces Cytotoxicity in Human Hepatocellular Carcinoma HepG2 Cell Line via Activation of the Extrinsic Pathway

Chaudhry GE, Sohimi NKA, Mohamad H, Zafar MN, Ahmed A, Sung YY, et al.

Asian Pac J Cancer Prev, 2021 Feb 01;22(S1):17-24.
PMID: 33576208 DOI: 10.31557/APJCP.2021.22.S1.17

OBJECTIVE: Liver cancer is one of the most common causes of cancer death, with reduced survival rates. The development of new chemotherapeutic agents is essential to find effective cytotoxic drugs that give minimum side effects to the surrounding healthy tissues. The main objective of the present study was to evaluate the cytotoxic effects and mechanism of cell death induced by the crude and diethyl ether extract of Xylocarpus mouccensis on the human hepatocellular carcinoma cell line.
METHODS: The cytotoxicity activity was measured using the MTS assay. The mode of cell death determined by the apoptosis study, DNA fragmentation analysis done by using the TUNEL system. The pathway study or mechanism of apoptosis observed by study caspases 8, 9, 3/7 Glo-caspases method.
RESULTS: In this study, the methanol extracts prepared from leaf Xylocarpus mouccensis leaf produced cytotoxicity effect with IC50 (72hr) < 30µg/ml. The IC50 value at 72 hours exerted by diethyl ether extract of Xylocarpus moluccensis leaf was 0.22 µg/ml, which was more cytotoxic than to that of crude methanol extract. The results obtained by the colorimetric TUNEL system suggest that methanol crude extract of Xylocarpus moluccensis (leaf), diethyl ether extract of Xylocarpus moluccensis (leaf) and methanol extract of Xylocarpus granatum (bark) induced DNA fragmentation in the HepG2 cell line. Besides, the caspase-Glo assay demonstrated that diethyl ether leaf extract of Xylocarpus moluccensis triggered apoptotic cell death via activation of caspases -8, and -3/7 However, no visible activation was noticed for caspase -9. Furthermore, TLC indicates the presence of potential metabolites in an extract of Xylocarpus moluccensis.
CONCLUSION: Thus, the present study suggests the remarkable potential of active metabolites in the extract of Xylocarpus moluccensis as a future therapeutic agent for the treatment of cancer.
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Fulltext Induction of Apoptosis by Acanthaster planci sp., and Diadema setosum sp., Fractions in Human Cervical Cancer Cell Line, HeLa

Chaudhry GE, Islamiah M, Zafar MN, Bakar K, Aziz N, Saidin J, et al.

Asian Pac J Cancer Prev, 2021 May 01;22(5):1365-1373.
PMID: 34048163 DOI: 10.31557/APJCP.2021.22.5.1365

Cancer is an uncontrolled multiplication of cells. The desire efficacy and severe toxicity of current anticancer drugs urge exploring and investigating a better alternative to existing chemotherapeutics. Natural products of marine origin are excellent sources of potential new drugs of enhanced biological activities.
OBJECTIVES: Thus, the cytotoxic effects along with investigating the mode of cell death exerted by fractions, AP-9, AP-THR, DS-8 and DS-9 fraction of Acanthaster planci, Diadema setosum sp., on the human cervical cancer cell line, HeLa.
METHODS: The cytotoxicity of fractions has determined by using an MTS assay. The early and late apoptosis was studied by using the High content Screening (HCS) instrument.
RESULTS: The four fractions produced effective cytotoxicity effects with IC50 values at 72hr of less than 20 μg/ml in the order of AP-9 > DS-9 > APTHR-9 > DS-8. The fraction s exhibited cytotoxicity via mediating apoptotic mode of cell death. The early apoptosis by exposure of phosphatidylserine to the outer leaflet of the plasma membrane and late apoptosis due to the presence of green stain (DNA fragmentation) in treated cells.
CONCLUSION: The potent bioactive compounds might be responsible for inducing apoptosis in cancer cells and, thus, the potential to be a successful candidate for exploring upcoming chemotherapeutic drugs.

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