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Fulltext Anti-Uterine Fibroid Effect of Standardized Labisia Pumila Var. Alata Extracts In Vitro and in Human Uterine Fibroid Cancer Xenograft Model

Zakaria N, Mohd KS, Ahmed Saeed MA, Ahmed Hassan LE, Shafaei A, Al-Suede FSR, et al.

Asian Pac J Cancer Prev, 2020 Apr 01;21(4):943-951.
PMID: 32334454 DOI: 10.31557/APJCP.2020.21.4.943

BACKGROUND: Uterine fibroids are a common type of solid tumor presenting in women of reproductive age. There are very few alternative treatment available from conventional treatment involving surgeries. Labisia pumila var. alata or locally known as 'Kacip Fatimah' was widely used as traditional medicine in Malaysia. This plant has been used to maintain a healthy female reproductive system. The present study aimed to evaluate anti fibroid potential of L. pumila extracts through in vitro apoptosis activity against uterine leiomyoma cells (SK-UT-1) and in uterine leiomyoma xenograft model. Evaluation of bioactive markers content were also carried out.
METHODS: Apoptotic induction of the extracts was determined by morphological examination of AO/PI dual staining assay by flourescent microscopy and flow cytometry analysis on Annexin V-FITC/PI stained cells. In vivo study was done in immune-compromised mouse xenograft model. HPLC analysis was employed to quantify marker compounds.
RESULTS: Morphological analysis showed L. pumila induced apoptosis in a dose dependent manner against SK-UT-1 cells. In vivo study indicated that L. pumila significantly suppressed the growth of uterine fibroid tumor. All tested extracts contain bioactive marker of gallic acid and cafeic acid.
CONCLUSION: This work provide significant data of the potential of L. pumila in management of uterine fibroids.
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Matched MeSH terms: Antineoplastic Agents/pharmacology*
Flavonoids with antiplasmodial and cytotoxic activities of Macaranga triloba

Zakaria I, Ahmat N, Jaafar FM, Widyawaruyanti A

Fitoterapia, 2012 Jul;83(5):968-72.
PMID: 22561914 DOI: 10.1016/j.fitote.2012.04.020

A new flavanone derivative, malaysianone A (1), four prenylated flavanones, 6-prenyl-3'-methoxyeriodictyol (2), nymphaeol B (3), nymphaeol C (4) and 6-farnesyl-3',4',5,7-tetrahydroxyflavanone (5), and two coumarins, 5,7-dihydroxycoumarin (6) and scopoletin (7), were isolated from the dichloromethane extract of the inflorescences of Macaranga triloba. The structures of these compounds were elucidated based on spectroscopic methods including nuclear magnetic resonance (NMR-1D and 2D), UV, IR and mass spectrometry. The cytotoxic activity of the compounds was tested against several cell lines, with 5 inhibiting very strongly the growth of HeLa and HL-60 cells (IC(50): 1.3 μg/ml and 3.3 μg/ml, respectively). Compound 5 also showed strong antiplasmodial activity (IC(50): 0.06 μM).

Matched MeSH terms: Antineoplastic Agents, Phytogenic/isolation & purification; Antineoplastic Agents, Phytogenic/pharmacology; Antineoplastic Agents, Phytogenic/therapeutic use*
Fulltext Reliability and validity of the Malay Version of the Breast- Impact of Treatment Scale (MVBITS) in breast cancer women undergoing chemotherapy

Zainal NZ, Shuib N, Bustam AZ, Sabki ZA, Guan NC

Asian Pac J Cancer Prev, 2013;14(1):463-8.
PMID: 23534774 DOI: 10.7314/apjcp.2013.14.1.463

BACKGROUND: Body image dissatisfaction among breast cancer survivors has been associated with psychological stress resultant from breast cancer and resultant surgery. This study aimed to examine the psychometric properties of the Malay Version of the Breast-Impact of Treatment Scale (MVBITS) and to investigate the associations of retained factors with the Hospital Anxiety and Depression Scale (HADS) and the Rosenberg Self-Esteem Scale (RSES).

MATERIALS AND METHODS: The MVBITS was 'forward-backward' translated from English to Malay and then administered to 70 female breast cancer patients who came to the Oncology Clinic of University Malaya Medical Centre, Kuala Lumpur, Malaysia to undergo chemotherapy. Principal component analysis (PCA) with varimax rotation was performed to explore the factor structure of the MVBITS. Associations of retained factors were estimated with reference to Spearman correlation coefficients.

RESULTS: The internal consistency reliability of MVBITS was good (Cronbach's alpha 0.945) and showed temporal stability over a 3-week period. Principal component analysis suggested two factors termed as 'Intrusion' and 'Avoidance' domains. These factors explained 70.3% of the variance. Factor 1 comprised the effects of breast cancer treatment on the emotion and thought, while Factor 2 informed attempts to limit exposure of the body to self or others. The Factor 1 of MVBITS was positively correlated with total, depression and anxiety sub-scores of HADS. Factor 2 was positively correlated with total and anxiety sub-scores of HADS. MVBITS was also positively correlated with the RSES scores.

CONCLUSIONS: The results showed that the Malay Version of Breast-Impact of Treatment Scale possesses satisfactory psychometric properties suggesting that this instrument is appropriate for assessment of body change stress among female breast cancer patients in Malaysia.

Matched MeSH terms: Antineoplastic Agents/adverse effects
Zerumbone targets the CXCR4-RhoA and PI3K-mTOR signaling axis to reduce motility and proliferation of oral cancer cells

Zainal NS, Gan CP, Lau BF, Yee PS, Tiong KH, Abdul Rahman ZA, et al.

Phytomedicine, 2018 Jan 15;39:33-41.
PMID: 29433681 DOI: 10.1016/j.phymed.2017.12.011

BACKGROUND: The CXCR4-RhoA and PI3K-mTOR signaling pathways play crucial roles in the dissemination and tumorigenesis of oral squamous cell carcinoma (OSCC). Activation of these pathways have made them promising molecular targets in the treatment of OSCC. Zerumbone, a bioactive monocyclic sesquiterpene isolated from the rhizomes of tropical ginger, Zingiber zerumbet (L.) Roscoe ex Sm. has displayed promising anticancer properties with the ability to modulate multiple molecular targets involved in carcinogenesis. While the anticancer activities of zerumbone have been well explored across different types of cancer, the molecular mechanism of action of zerumbone in OSCC remains largely unknown.
PURPOSE: Here, we investigated whether OSCC cells were sensitive towards zerumbone treatment and further determined the molecular pathways involved in the mechanism of action.
METHODS: Cytotoxicity, anti-proliferative, anti-migratory and anti-invasive effects of zerumbone were tested on a panel of OSCC cell lines. The mechanism of action of zerumbone was investigated by analysing the effects on the CXCR4-RhoA and PI3K-mTOR pathways by western blotting.
RESULTS: Our panel of OSCC cells was broadly sensitive towards zerumbone with IC50 values of less than 5 µM whereas normal keratinocyte cells were less responsive with IC50 values of more than 25 µM. Representative OSCC cells revealed that zerumbone inhibited OSCC proliferation and induced cell cycle arrest and apoptosis. In addition, zerumbone treatment inhibited migration and invasion of OSCC cells, with concurrent suppression of endogenous CXCR4 protein expression in a time and dose-dependent manner. RhoA-pull down assay showed reduction in the expression of RhoA-GTP, suggesting the inactivation of RhoA by zerumbone. In association with this, zerumbone also inhibited the PI3K-mTOR pathway through the inactivation of Akt and S6 proteins.
CONCLUSION: We provide evidence that zerumbone could inhibit the activation of CXCR4-RhoA and PI3K-mTOR signaling pathways leading to the reduced cell viability of OSCC cells. Our results suggest that zerumbone is a promising phytoagent for development of new therapeutics for OSCC treatment.

Matched MeSH terms: Antineoplastic Agents, Phytogenic/pharmacology
Fulltext Cytotoxic, Anti-Proliferative and Apoptosis Activity of l-Amino Acid Oxidase from Malaysian Cryptelytrops purpureomaculatus (CP-LAAO) Venom on Human Colon Cancer Cells

Zainal Abidin SA, Rajadurai P, Hoque Chowdhury ME, Othman I, Naidu R

Molecules, 2018 06 08;23(6).
PMID: 29890640 DOI: 10.3390/molecules23061388

The aim of this study is to investigate the potential anti-cancer activity of l-amino acid oxidase (CP-LAAO) purified from the venom of Cryptelytrops purpureomaculatus on SW480 and SW620 human colon cancer cells. Mass spectrometry guided purification was able to identify and purify CP-LAAO. Amino acid variations identified from the partial protein sequence of CP-LAAO may suggest novel variants of these proteins. The activity of the purified CP-LAAO was confirmed with o-phenyldiamine (OPD)-based spectrophotometric assay. CP-LAAO demonstrated time- and dose-dependent cytotoxic activity and the EC50 value was determined at 13 µg/mL for both SW480 and SW620 cells. Significant increase of caspase-3 activity, reduction of Bcl-2 levels, as well as morphological changes consistent with apoptosis were demonstrated by CP-LAAO. Overall, these data provide evidence on the potential anti-cancer activity of CP-LAAO from the venom of Malaysian C. purpureomaculatus for therapeutic intervention of human colon cancer.

Matched MeSH terms: Antineoplastic Agents/pharmacology*
Fulltext Alpinia zerumbet (Pers.): Food and Medicinal Plant with Potential In Vitro and In Vivo Anti-Cancer Activities

Zahra MH, Salem TAR, El-Aarag B, Yosri N, El-Ghlban S, Zaki K, et al.

Molecules, 2019 Jul 08;24(13).
PMID: 31288458 DOI: 10.3390/molecules24132495

BACKGROUND/AIM: Plants play an important role in anti-cancer drug discovery, therefore, the current study aimed to evaluate the biological activity of Alpinia zerumbet (A. zerumbet) flowers.
METHODS: The phytochemical and biological criteria of A. zerumbet were in vitro investigated as well as in mouse xenograft model.
RESULTS: A. zerumbet extracts, specially CH2Cl2 and MeOH extracts, exhibited the highest potent anti-tumor activity against Ehrlich ascites carcinoma (EAC) cells. The most active CH2Cl2 extract was subjected to bioassay-guided fractionation leading to isolatation of the naturally occurring 5,6-dehydrokawain (DK) which was characterized by IR, MS, 1H-NMR and 13C-NMR. A. zerumbet extracts, specially MeOH and CH2Cl2 extracts, exhibited significant inhibitory activity towards tumor volume (TV). Furthermore, A. zerumbet extracts declined the high level of malonaldehyde (MDA) as well as elevated the levels of superoxide dismutase (SOD) and catalase (CAT) in liver tissue homogenate. Moreover, DK showed anti-proliferative action on different human cancer cell lines. The recorded IC50 values against breast carcinoma (MCF-7), liver carcinoma (Hep-G2) and larynx carcinoma cells (HEP-2) were 3.08, 6.8, and 8.7 µg/mL, respectively.
CONCLUSION: Taken together, these findings open the door for further investigations in order to explore the potential medicinal properties of A. zerumbet.

Matched MeSH terms: Antineoplastic Agents, Phytogenic/pharmacology; Antineoplastic Agents, Phytogenic/chemistry*
Synthesis of Apoptotic New Quinazolinone-Based Compound and Identification of its Underlying Mitochondrial Signalling Pathway in Breast Cancer Cells

Zahedifard M, Faraj FL, Paydar M, Looi CY, Hasandarvish P, Hajrezaie M, et al.

Curr Pharm Des, 2015;21(23):3417-26.
PMID: 25808938

The anti-carcinogenic effect of the new quinazolinone compound, named MMD, was tested on MCF-7 human breast cancer cell line. The synthesis of quinazolinone-based compounds attracted strong attention over the past few decades as an alternative mean to produce analogues of natural products. Quinazolinone compounds sharing the main principal core structures are currently introduced in the clinical trials and pharmaceutical markets as anti-cancer agents. Thus, it is of high clinical interest to identify a new drug that could be used to control the growth and expansion of cancer cells. Quinazolinone is a metabolite derivative resulting from the conjugation of 2-aminobenzoyhydrazide and 5-methoxy-2- hydroxybenzaldehyde based on condensation reactions. In the present study, we analysed the influence of MMD on breast cancer adenoma cell morphology, cell cycle arrest, DNA fragmentation, cytochrome c release and caspases activity. MCF-7 is a type of cell line representing the breast cancer adenoma cells that can be expanded and differentiated in culture. Using different in vitro strategies and specific antibodies, we demonstrate a novel role for MMD in the inhibition of cell proliferation and initiation of the programmed cell death. MMD was found to increase cytochrome c release from the mitochondria to the cytosol and this effect was enhanced over time with effective IC50 value of 5.85 ± 0.71 μg/mL detected in a 72-hours treatment. Additionally, MMD induced cell cycle arrest at G0/G1 phase and caused DNA fragmentation with obvious activation of caspase-9 and caspases-3/7. Our results demonstrate a novel role of MMD as an anti-proliferative agent and imply the involvement of mitochondrial intrinsic pathway in the observed apoptosis.

Matched MeSH terms: Antineoplastic Agents/chemical synthesis*; Antineoplastic Agents/pharmacology*
Pd(II) complexes with chelating N-(1-alkylpyridin-4(1H)-ylidene)amide (PYA) ligands: Synthesis, characterization and evaluation of anticancer activity

Zafar MN, Butt AM, Chaudhry GE, Perveen F, Nazar MF, Masood S, et al.

J Inorg Biochem, 2021 11;224:111590.
PMID: 34507110 DOI: 10.1016/j.jinorgbio.2021.111590

The bidentate N-(1-Alkylpyridin-4(1H)-ylidene)amide (PYA) pro-ligands [H2LBn][Cl]2 (2), and [H2LMe][TfO]2 (3) were prepared by simple alkylation reactions of the known compound, N,N-di(pyridin-4-yl)oxalamide (H2L, 1). The Pd(II) complexes, [Pd(LBn)2][Cl]2 (4), [Pd(LMe)2][Cl][TfO] (5), Pd(LBn)Cl2 (6) and Pd(LMe)Cl2 (7) were synthesized through reactions between these pro-ligands and suitable Pd(II) substrates in the presence of base. The molecular structures of 3 and 6 were obtained by single crystal X-ray structure determinations. Studies of the experimental and computational DNA binding interactions of the compounds 1-7 revealed that overall 4 and 6 have the largest values for the binding parameters Kb and ΔGbo. The results showed a good correlation with the steric and electronic parameters obtained by quantitative structure activity relationship (QSAR) studies. In-vitro cytotoxicity studies against four different cell lines showed that the human breast cancer cell lines MCF-7, T47D and cervical cancer cell line HeLa had either higher or similar sensitivities towards 4, 6 and 2, respectively, compared to cisplatin. In general, the cytotoxicity of the compounds, represented by IC50 values, decreased in the order 4 > 6 > 2 > 5 > 3 > 1 > 7 in cancer cell lines. Apoptosis contributed significantly to the cytotoxic effects of these anticancer agents as evaluated by apoptosis studies.

Matched MeSH terms: Antineoplastic Agents/pharmacology*; Antineoplastic Agents/chemistry
Fulltext Combining PARP Inhibition with Platinum, Ruthenium or Gold Complexes for Cancer Therapy

Yusoh NA, Ahmad H, Gill MR

ChemMedChem, 2020 Nov 18;15(22):2121-2135.
PMID: 32812709 DOI: 10.1002/cmdc.202000391

Platinum drugs are heavily used first-line chemotherapeutic agents for many solid tumours and have stimulated substantial interest in the biological activity of DNA-binding metal complexes. These complexes generate DNA lesions which trigger the activation of DNA damage response (DDR) pathways that are essential to maintain genomic integrity. Cancer cells exploit this intrinsic DNA repair network to counteract many types of chemotherapies. Now, advances in the molecular biology of cancer has paved the way for the combination of DDR inhibitors such as poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) and agents that induce high levels of DNA replication stress or single-strand break damage for synergistic cancer cell killing. In this review, we summarise early-stage, preclinical and clinical findings exploring platinum and emerging ruthenium anti-cancer complexes alongside PARPi in combination therapy for cancer and also describe emerging work on the ability of ruthenium and gold complexes to directly inhibit PARP activity.

Matched MeSH terms: Antineoplastic Agents/chemical synthesis; Antineoplastic Agents/pharmacology*; Antineoplastic Agents/chemistry
Fulltext γ-Tocotrienol and 6-Gingerol in Combination Synergistically Induce Cytotoxicity and Apoptosis in HT-29 and SW837 Human Colorectal Cancer Cells

Yusof KM, Makpol S, Jamal R, Harun R, Mokhtar N, Ngah WZ

Molecules, 2015 Jun 03;20(6):10280-97.
PMID: 26046324 DOI: 10.3390/molecules200610280

Numerous bioactive compounds have cytotoxic properties towards cancer cells. However, most studies have used single compounds when bioactives may target different pathways and exert greater cytotoxic effects when used in combination. Therefore, the objective of this study was to determine the anti-proliferative effect of γ-tocotrienol (γ-T3) and 6-gingerol (6G) in combination by evaluating apoptosis and active caspase-3 in HT-29 and SW837 colorectal cancer cells. MTS assays were performed to determine the anti-proliferative and cytotoxicity effect of γ-T3 (0-150 µg/mL) and 6G (0-300 µg/mL) on the cells. The half maximal inhibitory concentration (IC50) value of 6G+ γ-T3 for HT-29 was 105 + 67 µg/mL and for SW837 it was 70 + 20 µg/mL. Apoptosis, active caspase-3 and annexin V FITC assays were performed after 24 h of treatment using flow cytometry. These bioactives in combination showed synergistic effect on HT-29 (CI: 0.89 ± 0.02,) and SW837 (CI: 0.79 ± 0.10) apoptosis was increased by 21.2% in HT-29 and 55.4% in SW837 (p < 0.05) after 24 h treatment, while normal hepatic WRL-68 cells were unaffected. Increased apoptosis by the combined treatments was also observed morphologically, with effects like cell shrinkage and pyknosis. In conclusion, although further studies need to be done, γ-T3 and 6G when used in combination act synergistically increasing cytotoxicity and apoptosis in cancer cells.

Matched MeSH terms: Antineoplastic Agents, Phytogenic/pharmacology*
Fulltext Green Synthesis of Fe3O4 Nanoparticles Stabilized by a Garcinia mangostana Fruit Peel Extract for Hyperthermia and Anticancer Activities

Yusefi M, Shameli K, Su Yee O, Teow SY, Hedayatnasab Z, Jahangirian H, et al.

Int J Nanomedicine, 2021;16:2515-2532.
PMID: 33824589 DOI: 10.2147/IJN.S284134

INTRODUCTION: Fe3O4 nanoparticles (Fe3O4 NPs) with multiple functionalities are intriguing candidates for various biomedical applications.
MATERIALS AND METHODS: This study introduced a simple and green synthesis of Fe3O4 NPs using a low-cost stabilizer of plant waste extract rich in polyphenols content with a well-known antioxidant property as well as anticancer ability to eliminate colon cancer cells. Herein, Fe3O4 NPs were fabricated via a facile co-precipitation method using the crude extract of Garcinia mangostana fruit peel as a green stabilizer at different weight percentages (1, 2, 5, and 10 wt.%). The samples were analyzed for magnetic hyperthermia and then in vitro cytotoxicity assay was performed.
RESULTS: The XRD planes of the samples were corresponding to the standard magnetite Fe3O4 with high crystallinity. From TEM analysis, the green synthesized NPs were spherical with an average size of 13.42±1.58 nm and displayed diffraction rings of the Fe3O4 phase, which was in good agreement with the obtained XRD results. FESEM images showed that the extract covered the surface of the Fe3O4 NPs well. The magnetization values for the magnetite samples were ranging from 49.80 emu/g to 69.42 emu/g. FTIR analysis verified the functional groups of the extract compounds and their interactions with the NPs. Based on DLS results, the hydrodynamic sizes of the Fe3O4 nanofluids were below 177 nm. Furthermore, the nanofluids indicated the zeta potential values up to -34.92±1.26 mV and remained stable during four weeks of storage, showing that the extract favorably improved the colloidal stability of the Fe3O4 NPs. In the hyperthermia experiment, the magnetic nanofluids showed the acceptable specific absorption rate (SAR) values and thermosensitive performances under exposure of various alternating magnetic fields. From results of in vitro cytotoxicity assay, the killing effects of the synthesized samples against HCT116 colon cancer cells were mostly higher compared to those against CCD112 colon normal cells. Remarkably, the Fe3O4 NPs containing 10 wt.% of the extract showed a lower IC50 value (99.80 µg/mL) in HCT116 colon cancer cell line than in CCD112 colon normal cell line (140.80 µg/mL).
DISCUSSION: This research, therefore, introduced a new stabilizer of Garcinia mangostana fruit peel extract for the biosynthesis of Fe3O4 NPs with desirable physiochemical properties for potential magnetic hyperthermia and colon cancer treatment.

Matched MeSH terms: Antineoplastic Agents/pharmacology*
Anti-proliferative and pro-apoptotic effects from sequenced combinations of andrographolide and cisplatin on ovarian cancer cell lines

Yunos NM, Mutalip SS, Jauri MH, Yu JQ, Huq F

Anticancer Res, 2013 Oct;33(10):4365-71.
PMID: 24123004

Andrographolide (Andro) is a diterpenoid that is isolated from Andrographis paniculata and reported to be active against several cancer cell lines. However, few in-depth studies have been carried out on its effects on ovarian cancer cell lines alone or in combination with cisplatin (Cis), which is commonly used to treat ovarian cancer. The aim of this study was to determine the anti-proliferative and apoptotic effects of Andro administered alone and in combination with Cis in the ovarian A2780 and A2780(cisR) cancer cell lines using five different sequences of administration (Cis/Andro h): 0/0h, 4/0 h, 0/4 h, 24/0 h and 0/24 h. The results were evaluated in terms of medium-effect dose (Dm) and combination indices (CI) using the CalcuSyn software. Unlike Cis, whose activity was lower in the resistant A2780(cisR) cell line than in the parent A2780 cell line, Andro was found to be three times more active in the A2780(cisR) cell line as compared to that in A2780 cell line. Synergism was observed when Cis and Andro were administered using the sequences 0/4 h and 4/0 h. The percentage of apoptotic cell death was found to be greater for the 0/4 h combination of Andro and Cis as compared to those values from single-drug treatments. The results may be clinically significant if confirmed in vivo.

Matched MeSH terms: Antineoplastic Agents/pharmacology*
Fulltext Applications of calixarenes in cancer chemotherapy: facts and perspectives

Yousaf A, Hamid SA, Bunnori NM, Ishola AA

Drug Des Devel Ther, 2015;9:2831-8.
PMID: 26082613 DOI: 10.2147/DDDT.S83213

Research on the therapeutic applications of calixarene derivatives is an emerging area of interest. The anticancer activity of various functionalized calixarenes has been reported by several research groups. Due to their superior geometric shape, calixarenes can accommodate drug molecules by forming inclusion complexes. Controlled release of anticancer drugs by calixarenes might help in targeted chemotherapy. This review summarizes the anticancer potential of the calixarenes and their drug loading properties. The potential use of calixarenes in chemoradiotherapy is also highlighted in brief.

Matched MeSH terms: Antineoplastic Agents/administration & dosage; Antineoplastic Agents/therapeutic use*
Benzimidazoles as new scaffold of sirtuin inhibitors: green synthesis, in vitro studies, molecular docking analysis and evaluation of their anti-cancer properties

Yoon YK, Ali MA, Wei AC, Shirazi AN, Parang K, Choon TS

Eur J Med Chem, 2014 Aug 18;83:448-54.
PMID: 24992072 DOI: 10.1016/j.ejmech.2014.06.060

Two series of novel benzimidazole derivatives were designed, synthesized and evaluated for their SIRT1 and SIRT2 inhibitory activity. Among the newly synthesized compounds, compound 4j displayed the best inhibitory activity for SIRT1 (IC50 = 54.21 μM) as well as for SIRT2 (IC50 = 26.85 μM). Cell proliferation assay showed that compound 4j possessed good antitumor activity against three different types of cancer cells derived from colon (HCT-116), breast (MDA-MB-468) and blood-leukemia (CCRF-CEM) with cell viability of 40.0%, 53.2% and 27.2% respectively at 50 μM. Docking analysis of representative compound 4j into SIRT2 indicated that the interaction with receptor was primarily due to hydrogen bonding and π-π stacking interactions.

Matched MeSH terms: Antineoplastic Agents/chemical synthesis; Antineoplastic Agents/metabolism; Antineoplastic Agents/pharmacology; Antineoplastic Agents/chemistry
Synthesis and evaluation of novel benzimidazole derivatives as sirtuin inhibitors with antitumor activities

Yoon YK, Ali MA, Wei AC, Choon TS, Osman H, Parang K, et al.

Bioorg Med Chem, 2014 Jan 15;22(2):703-10.
PMID: 24387981 DOI: 10.1016/j.bmc.2013.12.029

A total of 15 novel benzimidazole derivatives were designed, synthesized and evaluated for their SIRT1 and SIRT2 inhibitory activity. All compounds showed better inhibition on SIRT2 as compared to SIRT1. Among these, compound 5j displayed the best inhibitory activity for SIRT1 (IC50=58.43μM) as well as for SIRT2 (IC50=45.12μM). Cell cytotoxicity assays also showed that compound 5j possesses good antitumor activity against two different cancer cell lines derived from breast cancer (MCF-7 and MDA-MB-468). A simple structure-activity-relationship (SAR) study of the newly synthesized benzimidazole derivatives was also discussed.

Matched MeSH terms: Antineoplastic Agents/chemical synthesis; Antineoplastic Agents/pharmacology*; Antineoplastic Agents/chemistry
Fulltext Xanthohumol induces growth inhibition and apoptosis in ca ski human cervical cancer cells

Yong WK, Abd Malek SN

Evid Based Complement Alternat Med, 2015;2015:921306.
PMID: 25949267 DOI: 10.1155/2015/921306

We investigate induction of apoptosis by xanthohumol on Ca Ski cervical cancer cell line. Xanthohumol is a prenylated chalcone naturally found in hop plants, previously reported to be an effective anticancer agent in various cancer cell lines. The present study showed that xanthohumol was effective to inhibit proliferation of Ca Ski cells based on IC50 values using sulforhodamine B (SRB) assay. Furthermore, cellular and nuclear morphological changes were observed in the cells using phase contrast microscopy and Hoechst/PI fluorescent staining. In addition, 48-hour long treatment with xanthohumol triggered externalization of phosphatidylserine, changes in mitochondrial membrane potential, and DNA fragmentation in the cells. Additionally, xanthohumol mediated S phase arrest in cell cycle analysis and increased activities of caspase-3, caspase-8, and caspase-9. On the other hand, Western blot analysis showed that the expression levels of cleaved PARP, p53, and AIF increased, while Bcl-2 and XIAP decreased in a dose-dependent manner. Taken together, these findings indicate that xanthohumol-induced cell death might involve intrinsic and extrinsic apoptotic pathways, as well as downregulation of XIAP, upregulation of p53 proteins, and S phase cell cycle arrest in Ca Ski cervical cancer cells. This work suggests that xanthohumol is a potent chemotherapeutic candidate for cervical cancer.

Matched MeSH terms: Antineoplastic Agents
Molecular and Immunological Mechanisms Underlying the Various Pharmacological Properties of the Potent Bioflavonoid, Rutin

Yong DOC, Saker SR, Chellappan DK, Madheswaran T, Panneerselvam J, Choudhury H, et al.

Endocr Metab Immune Disord Drug Targets, 2020;20(10):1590-1596.
PMID: 32359343 DOI: 10.2174/1871530320666200503053846

The application of medicinal plants has captured the interest of researchers in recent times due to their potent therapeutic properties and a better safety profile. The prominent role of herbal products in treating and preventing multiple diseases dates back to ancient history and most of the modern drugs today originated from their significant sources owing to their ability to control multiple targets via different signalling pathways. Among them, flavonoids consist of a large group of polyphenols, which are well known for their various therapeutic benefits. Rutin is considered one of the attractive phytochemicals and important flavonoids in the pharmaceutical industry due to its diverse pharmacological activities via various underlying molecular mechanisms. It is usually prescribed for various disease conditions such as varicosities, haemorrhoids and internal haemorrhage. In this review, we have discussed and highlighted the different molecular mechanisms attributed to the various pharmacological activities of rutin, such as antioxidant, anti-inflammatory, anticancer, anti-allergic and antidiabetic. This review will be beneficial to herbal, biological and molecular scientists in understanding the pharmacological relevance of rutin at the molecular level.

Matched MeSH terms: Antineoplastic Agents, Phytogenic/pharmacology*
Anti-proliferative and anti-invasive properties of a purified fraction from Streptomyces sp. H7372

Yip WK, Cheenpracha S, Chang LC, Ho CC, Seow HF

Int J Oncol, 2010 Nov;37(5):1229-41.
PMID: 20878070

Secondary metabolites from actinomycetes especially the genus Streptomyces may be one of the most important sources for novel anticancer agents. A purified fraction from a novel actinomycete strain, Streptomyces sp. H7372, was elucidated in breast cancer cells. We have isolated three purified fractions from a novel strain, Streptomyces sp. H7372. One of the fractions, designated as 31-2, exhibited the strongest growth-inhibitory effect and thereby was selected for further studies. 31-2 exerted a growth-inhibitory effect on a panel of 15 human cancer and 2 non-malignant cell lines. In MCF-7 and MDA-MB-231 breast cancer cells, 31-2 induced a cytostatic (anti-proliferative) effect without causing cytotoxicity (cell death). Our data suggest that the cytostasis resulted from cell cycle arrest at the G1 phase in MCF-7 cells and at the S phase in MDA-MB-231 cells. Western blot analysis demonstrated a modulation of phosphorylation of the Rb and CDC2 proteins and of CDK4, cyclin D1 and cyclin D3 in the 31-2-treated breast cancer cell lines. The protein levels of CDK2, CDK6, and PCNA were not affected by 31-2 treatment. 31-2 also exhibited an anti-invasive effect in MDA-MB-231 cells. However, this effect is not attributed to the modulation of proteolytic activity in MDA-MB-231 cells as the enzymatic degradation of type IV collagen was not affected by 31-2. The 31-2 is a potent cytostatic and anti-invasive agent and modulates the cell cycle pathway. Together, these results will have important implications in searching for novel approaches to treat cancer.

Matched MeSH terms: Antineoplastic Agents/pharmacology*
Recent advancements in high-level synthesis of the promising clinical drug, prodigiosin

Yip CH, Yarkoni O, Ajioka J, Wan KL, Nathan S

Appl Microbiol Biotechnol, 2019 Feb;103(4):1667-1680.
PMID: 30637495 DOI: 10.1007/s00253-018-09611-z

Prodigiosin, a red linear tripyrrole pigment and a member of the prodiginine family, is normally secreted by the human pathogen Serratia marcescens as a secondary metabolite. Studies on prodigiosin have received renewed attention as a result of reported immunosuppressive, antimicrobial and anticancer properties. High-level synthesis of prodigiosin and the bioengineering of strains to synthesise useful prodiginine derivatives have also been a subject of investigation. To exploit the potential use of prodigiosin as a clinical drug targeting bacteria or as a dye for textiles, high-level synthesis of prodigiosin is a prerequisite. This review presents an overview on the biosynthesis of prodigiosin from its natural host Serratia marcescens and through recombinant approaches as well as highlighting the beneficial properties of prodigiosin. We also discuss the prospect of adopting a synthetic biology approach for safe and cost-effective production of prodigiosin in a more industrially compliant surrogate host.

Matched MeSH terms: Antineoplastic Agents/metabolism*
Potential CD34 signaling through phosphorylated-BAD in chemotherapy-resistant acute myeloid leukemia

Yiau SK, Lee C, Mohd Tohit ER, Chang KM, Abdullah M

J Recept Signal Transduct Res, 2019 Jun;39(3):276-282.
PMID: 31509041 DOI: 10.1080/10799893.2019.1660899

Acute myeloid leukemia (AML) constitutively express growth factors and cytokines for survival. Chemotherapy alters these signals to induce cell death. However, drug resistance in AML remains a major hindrance to successful treatment and early warning is unavailable. Modulation of signaling pathways during chemotherapy may provide a window to detect response and predict treatment outcome. Blood samples collected from AML patients before and at day-3 of induction therapy were compared for changes in expression of CD117, CD34, pro-inflammatory cytokines and mediators of Akt and MAPK pathways, using multi-color flow cytometry. Nine patients were diagnosed as drug-resistant and seven sensitive to chemotherapy. Twelve were paired. Average percentages of CD34 (66.8 ± 11.7% vs. 26.2 ± 5.8%, p = 0.033) and pBAD (66.9 ± 8.2% vs. 28.9 ± 8.2%, p = 0.016) were significantly increased in chemo-resistant (N = 9) compared to chemo-sensitive (N = 5) samples. Percentages of CD34 were strongly correlated with pBAD (R = 0.785; p = 0.001; N = 14) and pFKHR (R = 0.755; p = 0.002; N = 14) at day-3 induction. Chemo-sensitive cases expressed significantly higher percentages of IL-18Rα (71.9 ± 9.6% vs. 29.8 ± 5.8%, p = 0.016). Though not significantly different in the outcome, IL-1β was strongly associated with activated Akt-S473, IL-6 with phosphorylated JNK and FKHR while TNF-α appeared to trigger Bim, in treated samples. These preliminary results suggested AML cells resistant to chemotherapy increased expression of CD34 and may signal through pBAD while cells sensitive to chemotherapy-induced IL18Rα expression. These were observed early during induction therapy. Identifying CD34 is interesting as it is a convenient marker to monitor drug-resistance in AML patients. Inhibition of CD34 and pBAD signaling may be important in treating drug-resistant AML.

Matched MeSH terms: Antineoplastic Agents/pharmacology; Antineoplastic Agents/therapeutic use*

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