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  1. Doxorubicin-loaded micelles of amphiphilic diblock copolymer with pendant dendron improve antitumor efficacy: In vitro and in vivo studies
    Voon SH, Kue CS, Imae T, Saw WS, Lee HB, Kiew LV, et al.
    Int J Pharm, 2017 Dec 20;534(1-2):136-143.
    PMID: 29031979 DOI: 10.1016/j.ijpharm.2017.10.023
    Previously reported amphiphilic diblock copolymer with pendant dendron moieties (P71D3) has been further evaluated in tumor-bearing mice as a potential drug carrier. This P71D3-based micelle of an average diameter of 100nm was found to be biocompatible, non-toxic and physically stable in colloidal system up to 15days. It enhanced the in vitro potency of doxorubicin (DOX) in 4T1 breast tumor cells by increasing its uptake, by 3-fold, compared to free DOX. In 4T1 tumor-bearing mice, the tumor growth rate of P71D3/DOX (2mg/kg DOX equivalent) treated group was significantly delayed and their tumor volume was significantly reduced by 1.5-fold compared to those treated with free DOX. The biodistribution studies indicated that P71D3/DOX enhanced accumulation of DOX in tumor by 5- and 2-fold higher than free DOX treated mice at 15min and 1h post-administration, respectively. These results suggest that P71D3 micelle is a promising nanocarrier for chemotherapeutic agents.
    Matched MeSH terms: Doxorubicin/pharmacology*
  2. Fulltext Tert-butylhydroquinone attenuates doxorubicin-induced dysregulation of testicular cytoprotective and steroidogenic genes, and improves spermatogenesis in rats
    Ujah GA, Nna VU, Suleiman JB, Eleazu C, Nwokocha C, Rebene JA, et al.
    Sci Rep, 2021 Mar 09;11(1):5522.
    PMID: 33750916 DOI: 10.1038/s41598-021-85026-7
    Doxorubicin (DOX) is a broad-spectrum chemotherapeutic drug used in the treatment of cancers. It acts by generating reactive oxygen species in target cells. The actions are, however, not limited to cancerous cells as it attacks healthy cells, killing them. This study investigated the benefits of the antioxidant, tert-butylhydroquinone (tBHQ), on testicular toxicity following DOX therapy. Twenty-four adult male albino rats were assigned randomly into four groups (n = 6), namely: normal control (NC), tBHQ, DOX and tBHQ + DOX groups. tBHQ (50 mg/kg body weight in 1% DMSO) was administered orally for 14 consecutive days, while a single DOX dose (7 mg/kg body weight) was administered intraperitoneally on Day 8. DOX decreased sperm count, motility and viability, and decreased the levels of steroidogenesis-related proteins, and reproductive hormones. Furthermore, DOX decreased the expression of antioxidant cytoprotective genes, and decreased the protein level of proliferating cell nuclear antigen in the testis. Conversely, DOX increased the expression of pro-inflammatory and pro-apoptotic genes in the testis. These negative effects were ameliorated following the intervention with tBHQ. Our results suggest that tBHQ protects the testis and preserves both steroidogenesis and spermatogenesis in DOX-treated rats through the suppression of oxidative stress, inflammation and apoptosis.
    Matched MeSH terms: Doxorubicin/pharmacology
  3. Fulltext The strategy and clinical relevance of in vitro models of MAP resistance in osteosarcoma: a systematic review
    Tippett VL, Tattersall L, Ab Latif NB, Shah KM, Lawson MA, Gartland A
    Oncogene, 2023 Jan;42(4):259-277.
    PMID: 36434179 DOI: 10.1038/s41388-022-02529-x
    Over the last 40 years osteosarcoma (OS) survival has stagnated with patients commonly resistant to neoadjuvant MAP chemotherapy involving high dose methotrexate, adriamycin (doxorubicin) and platinum (cisplatin). Due to the rarity of OS, the generation of relevant cell models as tools for drug discovery is paramount to tackling this issue. Four literature databases were systematically searched using pre-determined search terms to identify MAP resistant OS cell lines and patients. Drug exposure strategies used to develop cell models of resistance and the impact of these on the differential expression of resistance associated genes, proteins and non-coding RNAs are reported. A comparison to clinical studies in relation to chemotherapy response, relapse and metastasis was then made. The search retrieved 1891 papers of which 52 were relevant. Commonly, cell lines were derived from Caucasian patients with epithelial or fibroblastic subtypes. The strategy for model development varied with most opting for continuous over pulsed chemotherapy exposure. A diverse resistance level was observed between models (2.2-338 fold) with 63% of models exceeding clinically reported resistance levels which may affect the expression of chemoresistance factors. In vitro p-glycoprotein overexpression is a key resistance mechanism; however, from the available literature to date this does not translate to innate resistance in patients. The selection of models with a lower fold resistance may better reflect the clinical situation. A comparison of standardised strategies in models and variants should be performed to determine their impact on resistance markers. Clinical studies are required to determine the impact of resistance markers identified in vitro in poor responders to MAP treatment, specifically with respect to innate and acquired resistance. A shift from seeking disputed and undruggable mechanisms to clinically relevant resistance mechanisms may identify key resistance markers that can be targeted for patient benefit after a 40-year wait.
    Matched MeSH terms: Doxorubicin/pharmacology
  4. Knockdown of ROS1 gene sensitizes breast tumor growth to doxorubicin in a syngeneic mouse model
    Tiash S, Chua MJ, Chowdhury EH
    Int J Oncol, 2016 Jun;48(6):2359-66.
    PMID: 27035628 DOI: 10.3892/ijo.2016.3452
    Treatment of breast cancer, the second leading cause of female deaths worldwide, with classical drugs is often accompanied by treatment failure and relapse of disease condition. Development of chemoresistance and drug toxicity compels compromising the drug concentration below the threshold level with the consequence of therapeutic inefficacy. Moreover, amplification and over-activation of proto-oncogenes in tumor cells make the treatment more challenging. The oncogene, ROS1 which is highly expressed in diverse types of cancers including breast carcinoma, functions as a survival protein aiding cancer progression. Thus we speculated that selective silencing of ROS1 gene by carrier-mediated delivery of siRNA might sensitize the cancer cells to the classical drugs at a relatively low concentration. In this investigation we showed that intracellular delivery of c-ROS1-targeting siRNA using pH-sensitive inorganic nanoparticles of carbonate apatite sensitizes mouse breast cancer cells (4T1) to doxorubicin, but not to cisplatin or paclitaxel, with the highest enhancement in chemosensitivity obtained at 40 nM of the drug concentration. Although intravenous administrations of ROS1-loaded nanoparticles reduced growth of the tumor, a further substantial effect on growth retardation was noted when the mice were treated with the siRNA- and Dox-bound particles, thus suggesting that silencing of ROS1 gene could sensitize the mouse breast cancer cells both in vitro and in vivo to doxorubicin as a result of synergistic effect of the gene knockdown and the drug action, eventually preventing activation of the survival pathway protein, AKT1. Our findings therefore provide valuable insight into the potential cross-talk between the pathways of ROS1 and doxorubicin for future development of effective therapeutics for breast cancer.
    Matched MeSH terms: Doxorubicin/pharmacology*
  5. siRNAs targeting multidrug transporter genes sensitise breast tumour to doxorubicin in a syngeneic mouse model
    Tiash S, Chowdhury EH
    J Drug Target, 2019 03;27(3):325-337.
    PMID: 30221549 DOI: 10.1080/1061186X.2018.1525388
    Chemotherapy, the commonly favoured approach to treat cancer is frequently associated with treatment failure and recurrence of disease as a result of development of multidrug resistance (MDR) with concomitant over-expression of drug efflux proteins on cancer cells. One of the most widely used drugs, doxorubicin (Dox) is a substrate of three different ATP-binding cassette (ABC) transporters, namely, ABCB1, ABCG2 and ABCC1, predominantly contributing to MDR phenotype in cancer. To silence these transporter-coding genes and thus enhance the therapeutic efficacy of Dox, pH-sensitive carbonate apatite (CA) nanoparticles (NPs) were employed as a carrier system to co-deliver siRNAs against these genes and Dox in breast cancer cells and in a syngeneic breast cancer mouse model. siRNAs and Dox were complexed with NPs by incubation at 37 °C and used to treat cancer cell lines to check cell viability and caspase-mediated signal. 4T1 cells-induced breast cancer mouse model was used for treatment with the complex to confirm their action in tumour regression. Smaller (∼200 nm) and less polydisperse NPs that were taken up more effectively by tumour tissue could enhance Dox chemosensitivity, significantly reducing the tumour size in a very low dose of Dox (0.34 mg/kg), in contrast to the limited effect observed in breast cancer cell lines. The study thus proposes that simultaneous delivery of siRNAs against transporter genes and Dox with the help of CA NPs could be a potential therapeutic intervention in effectively treating MDR breast cancer.
    Matched MeSH terms: Doxorubicin/pharmacology*
  6. Fulltext LMTK3 confers chemo-resistance in breast cancer
    Stebbing J, Shah K, Lit LC, Gagliano T, Ditsiou A, Wang T, et al.
    Oncogene, 2018 06;37(23):3113-3130.
    PMID: 29540829 DOI: 10.1038/s41388-018-0197-0
    Lemur tyrosine kinase 3 (LMTK3) is an oncogenic kinase that is involved in different types of cancer (breast, lung, gastric, colorectal) and biological processes including proliferation, invasion, migration, chromatin remodeling as well as innate and acquired endocrine resistance. However, the role of LMTK3 in response to cytotoxic chemotherapy has not been investigated thus far. Using both 2D and 3D tissue culture models, we found that overexpression of LMTK3 decreased the sensitivity of breast cancer cell lines to cytotoxic (doxorubicin) treatment. In a mouse model we showed that ectopic overexpression of LMTK3 decreases the efficacy of doxorubicin in reducing tumor growth. Interestingly, breast cancer cells overexpressing LMTK3 delayed the generation of double strand breaks (DSBs) after exposure to doxorubicin, as measured by the formation of γH2AX foci. This effect was at least partly mediated by decreased activity of ataxia-telangiectasia mutated kinase (ATM) as indicated by its reduced phosphorylation levels. In addition, our RNA-seq analyses showed that doxorubicin differentially regulated the expression of over 700 genes depending on LMTK3 protein expression levels. Furthermore, these genes were found to promote DNA repair, cell viability and tumorigenesis processes / pathways in LMTK3-overexpressing MCF7 cells. In human cancers, immunohistochemistry staining of LMTK3 in pre- and post-chemotherapy breast tumor pairs from four separate clinical cohorts revealed a significant increase of LMTK3 following both doxorubicin and docetaxel based chemotherapy. In aggregate, our findings show for the first time a contribution of LMTK3 in cytotoxic drug resistance in breast cancer.
    Matched MeSH terms: Doxorubicin/pharmacology
  7. Fulltext Graphene-based hybrid nanoparticle of doxorubicin for cancer chemotherapy
    SreeHarsha N, Maheshwari R, Al-Dhubiab BE, Tekade M, Sharma MC, Venugopala KN, et al.
    Int J Nanomedicine, 2019;14:7419-7429.
    PMID: 31686814 DOI: 10.2147/IJN.S211224
    Background: Prostate cancer (PC) has the highest prevalence in men and accounts for a high rate of neoplasia-related death. Doxorubicin (DOX) is one of the most widely used anti-neoplastic drugs for prostate cancer among others. However, it has low specificity and many side effects and affects normal cells. More recently, there have been newly developed drug delivery tools which are graphene or graphene-based, used to increase the specificity of the delivered drug molecules. The graphene derivatives possess both π-π stacking and increased hydrophobicity, factors that increase the likelihood of drug delivery. Despite this, the hydrophilicity of graphene remains problematic, as it induced problems with stability. For this reason, the use of a chitosan coating remains one way to modify the surface features of graphene.

    Method: In this investigation, a hybrid nanoparticle that consisted of a DOX-loaded reduced graphene oxide that is stabilized with chitosan (rGOD-HNP) was developed.

    Result: The newly developed rGOD-HNP demonstrated high biocompatibility and efficiency in entrapping DOX (~65%) and releasing it in a controlled manner (~50% release in 48 h). Furthermore, it was also demonstrated that rGOD-HNP can intracellularly deliver DOX and more specifically in PC-3 prostate cancer cells.

    Conclusion: This delivery tool offers a feasible and viable method to deliver DOX photo-thermally in the treatment of prostate cancer.

    Matched MeSH terms: Doxorubicin/pharmacology
  8. Cyclodextrin- and dendrimer-conjugated graphene oxide as a nanocarrier for the delivery of selected chemotherapeutic and photosensitizing agents
    Siriviriyanun A, Tsai YJ, Voon SH, Kiew SF, Imae T, Kiew LV, et al.
    Mater Sci Eng C Mater Biol Appl, 2018 Aug 01;89:307-315.
    PMID: 29752102 DOI: 10.1016/j.msec.2018.04.020
    In this study, nanohybrid materials consisting of graphene oxide (GO), β‑cyclodextrin (CD) and poly(amido amine) dendrimer (DEN) were successfully prepared by covalent bonding. GO-CD and GO-CD-DEN were found to be potential nanocarriers for anticancer drugs including chemotherapeutics (doxorubicin (DOX), camptothecin (CPT)) and photosensitizer (protoporphyrin IX (PpIX)). GO-CD possessed 1.2 times higher DOX-loading capacity than GO due to inclusion of additional DOX to the CD. The drug loading on GO-CD-DEN increased in the order: DOX 
    Matched MeSH terms: Doxorubicin/pharmacology
  9. Fulltext Modulation of P2Y6R expression exacerbates pressure overload-induced cardiac remodeling in mice
    Shimoda K, Nishimura A, Sunggip C, Ito T, Nishiyama K, Kato Y, et al.
    Sci Rep, 2020 08 18;10(1):13926.
    PMID: 32811872 DOI: 10.1038/s41598-020-70956-5
    Cardiac tissue remodeling caused by hemodynamic overload is a major clinical outcome of heart failure. Uridine-responsive purinergic P2Y6 receptor (P2Y6R) contributes to the progression of cardiovascular remodeling in rodents, but it is not known whether inhibition of P2Y6R prevents or promotes heart failure. We demonstrate that inhibition of P2Y6R promotes pressure overload-induced sudden death and heart failure in mice. In neonatal cardiomyocytes, knockdown of P2Y6R significantly attenuated hypertrophic growth and cell death caused by hypotonic stimulation, indicating the involvement of P2Y6R in mechanical stress-induced myocardial dysfunction. Unexpectedly, compared with wild-type mice, deletion of P2Y6R promoted pressure overload-induced sudden death, as well as cardiac remodeling and dysfunction. Mice with cardiomyocyte-specific overexpression of P2Y6R also exhibited cardiac dysfunction and severe fibrosis. In contrast, P2Y6R deletion had little impact on oxidative stress-mediated cardiac dysfunction induced by doxorubicin treatment. These findings provide overwhelming evidence that systemic inhibition of P2Y6R exacerbates pressure overload-induced heart failure in mice, although P2Y6R in cardiomyocytes contributes to the progression of cardiac fibrosis.
    Matched MeSH terms: Doxorubicin/pharmacology
  10. DNA Nanostructures Carrying Stoichiometrically Definable Antibodies
    Setyawati MI, Kutty RV, Leong DT
    Small, 2016 Oct;12(40):5601-5611.
    PMID: 27571230 DOI: 10.1002/smll.201601669
    Targeted drug delivery is one of the key challenges in cancer nanomedicine. Stoichiometric and spatial control over the antibodies placement on the nanomedicine vehicle holds a pivotal role to overcome this key challenge. Here, a DNA tetrahedral is designed with available conjugation sites on its vertices, allowing to bind one, two, or three cetuximab antibodies per DNA nanostructure. This stoichiometrically definable cetuximab conjugated DNA nanostructure shows enhanced targeting on the breast cancer cells, which results with higher overall killing efficacy of the cancer cells.
    Matched MeSH terms: Doxorubicin/pharmacology
  11. Cytotoxicity of cucurbitacin E from Citrullus colocynthis against multidrug-resistant cancer cells
    Saeed MEM, Boulos JC, Elhaboub G, Rigano D, Saab A, Loizzo MR, et al.
    Phytomedicine, 2019 Sep;62:152945.
    PMID: 31132750 DOI: 10.1016/j.phymed.2019.152945
    BACKGROUND: Cucurbitacin E (CuE) is an oxygenated tetracyclic triterpenoid isolated from the fruits of Citrullus colocynthis (L.) Schrad.

    PURPOSE: This study outlines CuE's cytotoxic activity against drug-resistant tumor cell lines. Three members of ABC transporters superfamily, P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) and ABCB5 were investigated, whose overexpression in tumors is tightly linked to multidrug resistance. Further factors of drug resistance studied were the tumor suppressor TP53 and the epidermal growth factor receptor (EGFR).

    METHODS: Cytotoxicity assays (resazurin assays) were used to investigate the activity of Citrullus colocynthis and CuE towards multidrug resistant cancer cells. Molecular docking (In silico) has been carried out to explore the CuE's mode of binding to ABC transporters (P-gp, BCRP and ABCB5). The visualization of doxorubicin uptake was done by a Spinning Disc Confocal Microscope. The assessment of proteins expression was done by western blotting analysis. COMPARE and hierarchical cluster analyses were applied to identify, which genes correlate with sensitivity or resistance to cucurbitacins (CuA, CuB, CuE, CuD, CuI, and CuK).

    RESULTS: Multidrug-resistant cells overexpressing P-gp or BCRP were cross-resistant to CuE. By contrast, TP53 knock-out cells were sensitive to CuE. Remarkably, resistant cells transfected with oncogenic ΔEGFR or ABCB5 were hypersensitive (collateral sensitive) to CuE. In silico analyses demonstrated that CuE is a substrate for P-gp and BCRP. Immunoblot analyses highlighted that CuE targeted EGFR and silenced its downstream signaling cascades. The most striking result that emerged from the doxorubicin uptake by ABCB5 overexpressing cells is that CuE is an effective inhibitor for ABCB5 transporter when compared with verapamil. The COMPARE analyses of transcriptome-wide expression profiles of tumor cell lines of the NCI identified common genes involved in cell cycle regulation, cellular adhesion and intracellular communication for different cucurbitacins.

    CONCLUSION: CuE represents a potential therapeutic candidate for the treatment of certain types of refractory tumors. To best of our knowledge, this is the first time to identify CuE and verapamil as inhibitors for ABCB5 transporter.

    Matched MeSH terms: Doxorubicin/pharmacology
  12. Fulltext Development and characterization of liposomal doxorubicin hydrochloride with palm oil
    Sabeti B, Noordin MI, Mohd S, Hashim R, Dahlan A, Javar HA
    Biomed Res Int, 2014;2014:765426.
    PMID: 24795894 DOI: 10.1155/2014/765426
    The usage of natural products in pharmaceuticals has steadily seen improvements over the last decade, and this study focuses on the utilization of palm oil in formulating liposomal doxorubicin (Dox). The liposomal form of Dox generally minimizes toxicity and enhances target delivery actions. Taking into account the antiproliferative and antioxidant properties of palm oil, the aim of this study is to design and characterize a new liposomal Dox by replacing phosphatidylcholine with 5% and 10% palm oil content. Liposomes were formed using the freeze_thaw method, and Dox was loaded through pH gradient technique and characterized through in vitro and ex vivo terms. Based on TEM images, large lamellar vesicles (LUV) were formed, with sizes of 438 and 453 nm, having polydispersity index of 0.21 ± 0.8 and 0.22 ± 1.3 and zeta potentials of about -31 and -32 mV, respectively. In both formulations, the entrapment efficiency was about 99%, and whole Dox was released through 96 hours in PBS (pH = 7.4) at 37°C. Comparing cytotoxicity and cellular uptake of LUV with Caelyx(R) on MCF7 and MDA-MBA 231 breast cancer cell lines indicated suitable uptake and lower IC50 of the prepared liposomes.
    Matched MeSH terms: Doxorubicin/pharmacology
  13. Fulltext Scalable Production of Recombinant Membrane Active Peptides and Its Potential as a Complementary Adjunct to Conventional Chemotherapeutics
    Rothan HA, Ambikabothy J, Abdulrahman AY, Bahrani H, Golpich M, Amini E, et al.
    PLoS One, 2015;10(9):e0139248.
    PMID: 26418816 DOI: 10.1371/journal.pone.0139248
    The production of short anticancer peptides in recombinant form is an alternative method for costly chemical manufacturing. However, the limitations of host toxicity, bioactivity and column purification have impaired production in mass quantities. In this study, short cationic peptides were produced in aggregated inclusion bodies by double fusion with a central protein that has anti-cancer activity. The anticancer peptides Tachiplicin I (TACH) and Latarcin 1 (LATA) were fused with the N- and C-terminus of the MAP30 protein, respectively. We successfully produced the recombinant TACH-MAP30-LATA protein and MAP30 alone in E. coli that represented 59% and 68% of the inclusion bodies. The purified form of the inclusion bodies was prepared by eliminating host cell proteins through multiple washing steps and semi-solubilization in alkaline buffer. The purified active protein was recovered by inclusive solubilization at pH 12.5 in the presence of 2 M urea and refolded in alkaline buffer containing oxides and reduced glutathione. The peptide-fusion protein showed lower CC50 values against cancer cells (HepG2, 0.35±0.1 μM and MCF-7, 0.58±0.1 μM) compared with normal cells (WRL68, 1.83±0.2 μM and ARPE19, 2.5±0.1 μM) with outstanding activity compared with its individual components. The presence of the short peptides facilitated the entry of the peptide fusion protein into cancer cells (1.8 to 2.2-fold) compared with MAP30 alone through direct interaction with the cell membrane. The cancer chemotherapy agent doxorubicin showed higher efficiency and selectivity against cancer cells in combination with the peptide- fusion protein. This study provides new data on the mass production of short anticancer peptides as inclusion bodies in E. coli by fusion with a central protein that has similar activity. The product was biologically active against cancer cells compared with normal cells and enhanced the activity and selective delivery of an anticancer chemotherapy agent.
    Matched MeSH terms: Doxorubicin/pharmacology
  14. Effect of recombinant human erythropoietin and doxorubicin in combination on the proliferation of MCF-7 and MDA-MB231 breast cancer cells
    Radwan EM, Abdullah R, Al-Qubaisi MS, El Zowalaty ME, Naadja SE, Alitheen NB, et al.
    Mol Med Rep, 2016 May;13(5):3945-52.
    PMID: 26987078 DOI: 10.3892/mmr.2016.4989
    Patients with cancer often exhibit signs of anemia as the result of the disease. Thus, cancer chemotherapies often include erythropoietin (EPO) in the regime to improve the survival rate of these patients. The aim of the present study was to determine the effect of EPO on doxorubicin-treated breast cancer cells. The cytotoxicity of doxorubicin alone or in combination with EPO against the MCF-7 and MDA-MB‑231 human breast cancer cells were determined using an MTT cell viability assay, neutral red (NR) uptake assay and lactate dehydrogenase (LDH) assay. The estimated half maximal inhibitory concentration values for doxorubicin and the combination of doxorubicin with EPO were between 0.140 and 0.260 µg/ml for all cells treated for 72 h. Treatment with doxorubicin in combination with EPO led to no notable difference in cytotoxicity, compared with treatment with doxorubicin alone. The antiproliferative effect of doxorubicin at a concentration of 1 µg/ml on the MDA‑MB‑231 cells was demonstrated by the decrease in viable cells from 3.6x10(5) at 24 h to 2.1x10(5) at 72 h of treatment. In order to confirm apoptosis in the doxorubicin-treated cells, the activities of caspases-3/7 and ‑9 were determined using a TBE assay. The results indicated that the activities of caspases-3/7 and ‑9 were significantly elevated in the doxorubicin-treated MDA-MB-231 cells by 571 and 645%, respectively, and in the MCF 7 cells by 471 and 345%, respectively, compared with the control cells. EPO did not modify the effect of doxorubicin on these cell lines. The results of the present study suggested that EPO was safe for use in combination with doxorubicin in the treatment of patients with breast cancer and concurrent anemia.
    Matched MeSH terms: Doxorubicin/pharmacology
  15. Isolation and bioactivities of constitutents of the roots of Garcinia atroviridis
    Permana D, Lajis NH, Mackeen MM, Ali AM, Aimi N, Kitajima M, et al.
    J Nat Prod, 2001 Jul;64(7):976-9.
    PMID: 11473441
    Two new prenylated compounds, the benzoquinone atrovirinone (1) and the depsidone atrovirisidone (2), were isolated from the roots of Garcinia atroviridis. Their structures were determined on the basis of the analysis of spectroscopic data. While compound 2 showed some cytotoxicity against HeLa cells, both compounds 1 and 2 were only mildly inhibitory toward Bacillus cereus and Staphylococcus aureus.
    Matched MeSH terms: Doxorubicin/pharmacology
  16. Selectivity of compounds isolated from the leaves of Nerium indicum Mill. on various human cancer cell lines
    Mae SH, Sofia M, Bolhuis RL, Nooter K, Oostrum RG, Subagus W, et al.
    Med J Malaysia, 2008 Jul;63 Suppl A:24-5.
    PMID: 19024965
    The leaves of Nerium indicum Mill. have been utilized traditionally to cure cancer. By Bioassay (BST) guided isolation method, six compounds were isolated from the CHCl3 extract of the leaves. Selectivity of these compounds (in 0.6-12,500 ng/ml) was tested on various human cancer (MCF7, EVSA-T, T47D, H226, IGROV, A498, WIDR, M19, HeLa) and normal (Vero) cells in vitro. Doxorubicin and cysplatin were used as positive controls. The result indicated that NiO2D (5alpha-oleandrin) possessed the best cytotoxic effect on HeLa cells (IC50, 8.38 x10(-6) mM) and NiO2C (16, 17-dehidrodeasetil-5alpha-oleandrin) on A498 cells (IC50, 1.43 x 10(-6) mM). Those two compounds were not cytotoxic to normal cell.
    Matched MeSH terms: Doxorubicin/pharmacology
  17. Fulltext Modulating multidrug resistance gene in leukaemia cells by short interfering RNA
    Lim MN, Lau NS, Chang KM, Leong CF, Zakaria Z
    Singapore Med J, 2007 Oct;48(10):932-8.
    PMID: 17909680
    The multidrug resistance gene, MDR1, is one of the genes responsible for resistance to chemotherapy in the treatment of leukaemia and other cancers. The discovery of RNA interference in mammalian cells has provided a powerful tool to inhibit the expression of this gene. However, very little is known about the transfection of leukaemia cells with short interfering RNA (siRNA) targeted at MDR1. This study aims to evaluate the effectiveness of two chemically-synthesised siRNA in modulating MDR1 gene and inhibiting P-glycoprotein expression in leukaemic cells. We also evaluated two siRNA delivery methods in this study.
    Matched MeSH terms: Doxorubicin/pharmacology
  18. Fulltext In vitro delivery and controlled release of Doxorubicin for targeting osteosarcoma bone cancer
    Kamba SA, Ismail M, Hussein-Al-Ali SH, Ibrahim TA, Zakaria ZA
    Molecules, 2013 Aug 30;18(9):10580-98.
    PMID: 23999729 DOI: 10.3390/molecules180910580
    Drug delivery systems are designed to achieve drug therapeutic index and enhance the efficacy of controlled drug release targeting with specificity and selectivity by successful delivery of therapeutic agents at the desired sites without affecting the non-diseased neighbouring cells or tissues. In this research, we developed and demonstrated a bio-based calcium carbonate nanocrystals carrier that can be loaded with anticancer drug and selectively deliver it to cancer cells with high specificity by achieving the effective osteosarcoma cancer cell death without inducing specific toxicity. The results showed pH sensitivity of the controlled release characteristics of the drug at normal physiological pH 7.4 with approximately 80% released within 1,200 min but when exposed pH 4.8 the corresponding 80% was released in 50 min. This study showed that the DOX-loaded CaCO₃ nanocrystals have promising applications in delivery of anticancer drugs.
    Matched MeSH terms: Doxorubicin/pharmacology
  19. Fulltext In vitro ultrastructural changes of MCF-7 for metastasise bone cancer and induction of apoptosis via mitochondrial cytochrome C released by CaCO3/Dox nanocrystals
    Kamba AS, Ismail M, Ibrahim TA, Zakaria ZA, Gusau LH
    Biomed Res Int, 2014;2014:391869.
    PMID: 25028650 DOI: 10.1155/2014/391869
    Bones are the most frequent site for breast cancer cells to settle and spread (metastasise); bone metastasis is considered to have a substantial impact on the quality of patients with common cancers. However, majority of breast cancers develop insensitivity to conventional chemotherapy which provides only palliation and can induce systemic side effects. In this study we evaluated the effect of free Dox and CaCO3/Dox nanocrystal on MCF-7 breast cancer using MTT (3-[4, 5-dimethylthiazol-2-yl]-2, 5-diphenyl tetrazolium bromide), neural red, and lactate dehydrogenase colorimetric assays while DNA fragmentation and BrdU genotoxicity were also examined. Apoptogenic protein Bax, cytochrome C, and caspase-3 protein were analysed. Morphological changes of MCF-7 were determined using contrast light microscope and scanning and transmission electron microscope (SEM and TEM). The findings of the analysis revealed higher toxicity of CaCO3/Dox nanocrystal and effective cells killing compared to free Dox, morphological changes such as formation of apoptotic bodies, membrane blebbing, and absent of microvilli as indicated by the SEM analysis while TEM revealed the presence of chromatin condensation, chromosomal DNA fragmentation, cell shrinkage, and nuclear fragmentation. Results of TUNEL assay verified that most of the cells undergoes apoptosis by internucleosomal fragmentation of genomic DNA whereas the extent of apoptotic cells was calculated using the apoptotic index (AI). Therefore, the biobased calcium carbonate nanocrystals such as Dox carriers may serve as an alternative to conventional delivery system.
    Matched MeSH terms: Doxorubicin/pharmacology*
  20. Fulltext Cockle Shell-Derived Aragonite CaCO3 Nanoparticles for Co-Delivery of Doxorubicin and Thymoquinone Eliminates Cancer Stem Cells
    Ibiyeye KM, Zuki ABZ
    Int J Mol Sci, 2020 Mar 10;21(5).
    PMID: 32164352 DOI: 10.3390/ijms21051900
    Cancer stem cells CSCs (tumour-initiating cells) are responsible for cancer metastasis and recurrence associated with resistance to conventional chemotherapy. This study generated MBA MD231 3D cancer stem cells enriched spheroids in serum-free conditions and evaluated the influence of combined doxorubicin/thymoquinone-loaded cockle-shell-derived aragonite calcium carbonate nanoparticles. Single loaded drugs and free drugs were also evaluated. WST assay, sphere forming assay, ALDH activity analysis, Surface marker of CD44 and CD24 expression, apoptosis with Annexin V-PI kit, cell cycle analysis, morphological changes using a phase contrast light microscope, scanning electron microscopy, invasion assay and migration assay were carried out; The combination therapy showed enhanced apoptosis, reduction in ALDH activity and expression of CD44 and CD24 surface maker, reduction in cellular migration and invasion, inhibition of 3D sphere formation when compared to the free drugs and the single drug-loaded nanoparticle. Scanning electron microscopy showed poor spheroid formation, cell membrane blebbing, presence of cell shrinkage, distortion in the spheroid architecture; and the results from this study showed that combined drug-loaded cockle-shell-derived aragonite calcium carbonate nanoparticles can efficiently destroy the breast CSCs compared to single drug-loaded nanoparticle and a simple mixture of doxorubicin and thymoquinone.
    Matched MeSH terms: Doxorubicin/pharmacology*
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