METHODS: By utilizing a panel of breast cancer cells and mammospheres culture as cell-based screening platforms, we performed high-throughput chemical library screens to identify agents that are effective against breast CSCs and non-CSCs. The hit molecules were paired with conventional chemotherapy to evaluate the combinatorial treatment effects on breast CSCs and non-CSCs.
RESULTS: We identified a total of 193 inhibitors that effectively targeting both breast CSCs and non-CSCs. We observed that histone deacetylase inhibitors (HDACi) synergized conventional chemotherapeutic agents (i.e., doxorubicin and cisplatin) in targeting breast CSCs and non-CSCs simultaneously. Further analyses revealed that quisinostat, a potent inhibitor for class I and II HDACs, potentiated doxorubicin-induced cytotoxicity in both breast CSCs and non-CSCs derived from the basal-like (MDA-MB-468 and HCC38), mesenchymal-like (MDA-MB-231), and luminal-like breast cancer (MCF-7). It was also observed that the basal-like breast CSCs and non-CSCs were more sensitive to the co-treatment of quisinostat with doxorubicin compared to that of the luminal-like breast cancer subtype.
CONCLUSION: In conclusion, this study demonstrates the potential of HDACi as therapeutic options, either as monotherapy or in combination with chemotherapeutics against refractory breast cancer.
OBJECTIVE: We have successfully prepared mixed fatty acid liposomes from two monounsaturated fatty acids, namely oleic acid and erucic acid, which stabilised by DOPEPEG2000. The Critical Vesicular Concentration (CVC) of liposomes was found to be within 0.09 to 0.21 mmol dm-3, with an average particle size of 400 nm.
METHODS: Encapsulation of various anticancer drugs such as folinic acid, methotrexate, doxorubicin, or irinotecan resulted in Encapsulation Efficiency (%EE) of up to 90%. Using a 3-(4, 5-dimethylthiazol-2- yl)-2,5-diphenyltetrazolium bromide (MTT) assay, the median Inhibitory Concentration (IC50) values of mixed oleic acid-erucic acid encapsulating hydrophilic drugs was remarkably reduced at the end of 24 hours of incubation with the human lung carcinoma cell line A549.
RESULTS: The results suggest that mixed oleic acid-erucic acid liposomes are a potential new approach to further develop as an alternative vehicle of various drugs for cancer treatment.
METHODS: In this study, CD24 population from the MCF-7 spheroid was sorted and subjected to spheroid formation test, stem cell markers immunofluorescence, invasion and migration test as well as microRNA expression profiling.
RESULTS: Sorted MCF-7 CD24 cells from primary spheroids were able to reform its 3D spheroid shape after 7 days in non-adherent culture conditions. In contrast to the primary spheroids, the expression of SOX-2, CD44, CD49f and Nanog were dim in MCF-7 CD24+ cells. Remarkably, MCF-7 CD24 cells were found to show high expression of ALDH1 protein which may have resulted in these cells exhibiting higher resistance against doxorubicin and cisplatin when compared to that of the parental cells. Moreover, microRNA profiling has shown that the absence of cancer stem cell properties were consistent with the downregulation of major cancer stem cells related pathways including Hedgehog, Wnt and MAPK signalling pathways. However, the upregulated pathways such as adherans junctions, focal adhesion and tight junction suggest that CD24+ cells were probably at an epithelial-like state of cell transition.
CONCLUSION: In conclusion, neglected CD24+ cells in MCF-7 spheroid did not exhibit typical breast CSCs properties. The presence of miRNAs and their analysed pathways suggested that these cells could be a distinct intermediate cell state in breast CSCs.
METHODS: 79 patients with DLBCL (nodal, 59% and extranodal, 41%) treated with rituximab combined with cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) therapy were selected. Expression levels of BCR and linked signalling pathway molecules were inter-related with Lymph2Cx-based cell of origin (COO) types and overall survival (OS).
RESULTS: Activated B-cell (ABC) type DLBCL constituted 49% (39/79) compared with germinal centre B-cell (GCB) type DLBCL (29/79; 37%) and revealed poor prognosis (p=0.013). In ABC-DLBCL, high BTK expression exerted poor response to R-CHOP, while OS in ABC-DLBCL with low BTK expression was similar to GCB-DLBCL subtype (p=0.004). High LYN expression coupled with a poor OS for ABC-DLBCL as well as GCB-DLBCL subtypes (p=0.001). Furthermore, high coexpression of BTK/LYN (BTKhigh/LYNhigh) showed poor OS (p=0.019), which linked with upregulation of several genes associated with BCR repertoire and nuclear factor-kappa B pathway (p<0.01). In multivariate analysis, high BTK and LYN expression retained prognostic significance against established clinical predictive factors such as age, International Prognostic Index and COO (p<0.05).
CONCLUSIONS: Our data provide a clear association between high BCR activity in DLBCL and response to therapy in a distinct population. Molecular data provided here will pave the pathway for the provision of promising novel-targeted therapies to patients with DLBCL in Southeast Asia.
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.
AIM OF THE STUDY: To develop a natural biodegradable macromolecule i.e. Chitosan (CS)-coated-DAUN-PLGA-poly(lactic-co-glycolic acid)-Nanoparticles (NPs) with an aim to improve oral-DAUN bioavailability and to develop as well as validate UHPLC-MS/MS (ESI/Q-TOF) method for plasma quantification and pharmacokinetic analysis (PK) of DAUN.
RESULTS: A particle size (198.3 ± 9.21 nm), drug content (47.06 ± 1.16 mg/mg) and zeta potential (11.3 ± 0.98 mV), consisting of smooth and spherical shape was observed for developed formulation. Cytotoxicity studies for CS-DAUN-PLGA-NPs revealed; a comparative superiority over free DAUN-S (i.v.) in human breast adenocarcinoma cell lines (MCF-7) and a higher permeability i.e. 3.89 folds across rat ileum, as compared to DAUN-PLGA-NPs (p Doxorubicin, for elution time and transition, respectively.
CONCLUSION: A novel natural biodegradable approach used in the preparation of CS coated DAUN-NPs for oral administration of DAUN is reported in this study which is can be utilized as an alternate for intravenous therapy.
Methods: In this study, the MKN28 and MKN74 GC cell lines were treated with ethanol extracts of Allium angulosum L., Allium lusitanicum Lam., Allium sativum L. (from Malaysia and Poland), Allium tibeticum Rendle and Allium ursinum L. The cytotoxicity of the extracts and their influence on COX2 and CDH1 mRNA and protein expression were evaluated as well as their influence on doxorubicin's (DOX) efficacy - a drug that has been used in GC treatment.
Results: Among the tested species, ethanol extracts of A. sativum L. (Poland and Malaysia), A. tibeticum Rendle and A. ursinum L. influenced the levels of CDH1 and COX2, but only in the MKN74 cell line. Thus, it is possible that tumours with increased COX2 expression will be more susceptible to garlic treatment. Observed phenomenon was independent of Allium extract's toxicity. In comparison to DOX, tested extracts were more toxic. Moreover, A. sativum revealed synergistic effect with the drug.
Conclusion: In conclusion, the results indicate the potential application of Allium genus to GC chemoprevention and treatment support through CDH restoration and COX2 downregulation. This issue needs further investigations as it might be used in clinics.
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.