Background Here, we examined the tumoricidal effect of Gemini surfactant nanoparticles enriched with curcumin on 3D spheroid HT-29 cells. The delivery of curcumin and other phytocompounds to the tumor niche is an important challenge. Methods Spheroid HT-29 cells were generated by using a conventional hanging drop method and exposed to different concentrations of Gemini-curcumin nanoparticles. The changes in spheroid integrity and cell viability were evaluated by measuring the spheroid diameter and LDH release, respectively. The uptake of Gemini-curcumin nanoparticles was detected by flow cytometry assay. Flow cytometric of Rhodamine 123 efflux was also performed. Migration capacity was analyzed using a Transwell insert assay. By using real-time PCR analysis and Western blotting, we studied the expression level of MMP-2, -9, Vimentin, and E-cadherin genes. Results Gemini-curcumin nanoparticles had the potential to disintegrate spheroids and decrease central density compared to the control group (p < 0.05). These changes coincided with enhanced LDH release by the increase of nanoparticle concentration (p < 0.05). Data highlighted the ability of cells to uptake synthetic nanoparticles in a dose-dependent manner. We found reduced Rhodamine 123 efflux in treated HT-29 spheroid cells compared to the control (p < 0.05). Nanoparticles significantly decreased the metastasis and epithelial-mesenchymal transition (EMT) rate by the suppression of MMP-2 and MMP-9, Vimentin, and induction of E-cadherin (p < 0.05). Conclusion Our data confirmed that Gemini curcumin has the potential to suppress cell proliferation and inhibit metastasis in 3D spheroid HT-29 cells in vitro.
The p53 protein is a tumor suppressor encoded by the TP53 gene and consists of 393 amino acids with four main functional domains. This protein responds to various cellular stresses to regulate the expression of target genes, thereby causing DNA repair, cell cycle arrest, apoptosis, metabolic changes, and aging. Mutations in the TP53 gene and the functions of the wild-type p53 protein (wtp53) have been linked to various human cancers. Eight TP53 gene mutations are located in codons, constituting 28% of all p53 mutations. The p53 can be used as a biomarker for tumor progression and an excellent target for designing cancer treatment strategies. In wild-type p53-carrying cancers, abnormal signaling of the p53 pathway usually occurs due to other unusual settings, such as high MDM2 expression. These differences between cancer cell p53 and normal cells have made p53 one of the most important targets for cancer treatment. In this review, we have dealt with various issues, such as the relative contribution of wild-type p53 loss of function, including transactivation-dependent and transactivation-independent activities in oncogenic processes and their role in cancer development. We also discuss the role of p53 in the process of ferroptosis and its targeting in cancer treatment. Finally, we focus on p53-related drug delivery systems and investigate the challenges and solutions.
Background: Ovarian cancer has the highest mortality rate among gynecological malignancies. Despite recent advances in treatment, most patients still suffer from poor prognosis. Curcumin has shown highly cytotoxic effects against different types of cancer. However, its poor bioavailability restricts its clinical application. Gemini Curcumin (GeminiCur) has been developed to overcome this limitation. Objective: Here, we aimed to unravel the inhibitory effect of Gemini-Cur in ovarian cancer. Methods: OVCAR-3 cells were treated with free curcumin and Gemni-Cur in a time- and dose-dependent manner. Then, the anticancer activity was investigated by uptake kinetics, cellular viability and apoptotic assays. Furthermore, we evaluated the BAX/Bcl-2 expression ratio by real-time PCR and western blotting. Results: Our data showed that gemini surfactant nanoparticles enhance the cellular uptake of curcumin compared to free curcumin (p<0.01). Regarding the growth inhibitory effect of nano-curcumin, the results demonstrated that Gemini-Cur suppresses the proliferation of OVCAR-3 cells through induction of apoptosis (p<0.001). Conclusion: The results illustrate that Gemini-Cur nanoparticles have a great potential for developing novel therapeutics against ovarian cancer.
Background: Dendrosomal nano-curcumin (DNC) represents an enormous potential to serve as a therapeutic anticancer agent. Here, we investigated the effect of DNC on wild type- and p53-mutant breast cancer cells. Methods: MCF-7 and T47D cells were treated with DNC and investigated for cell viability through MTT assay. The mode of death was analyzed using Annexin V/FITC staining and PARP cleavage assays. Flow cytometric efflux and cell swelling tests were employed to assess the p-glycoprotein (P-gp) transporter activity. Moreover, real-time PCR was employed to study the expression of Bax, Bcl-2 as well as survivin and its ΔEx3 splicing variant. Results: Our findings confirmed that DNC repressed cancer cell proliferation by induction of apoptosis. Additionally, DNC significantly modulated P-gp function that might lead to improved cellular permanence of curcumin. Malfunction of P-gp activity by DNC demonstrates its capability in reducing the drug resistance of p53-mutant cancer cells. Conclusions: In conclusion, our findings demonstrated that dendrosomal nano-curcumin could be considered an anti-tumor therapeutic for p53-mutant tumor malignancies.
Colorectal cancer is one of the leading causes of cancer-related deaths worldwide. The gemini nanoparticle formulation of polyphenolic curcumin significantly inhibits the viability of cancer cells. However, the molecular mechanisms and pathways underlying its toxicity in colon cancer are unclear. Here, we aimed to uncover the possible novel targets of gemini curcumin (Gemini-Cur) on colorectal cancer and related cellular pathways. After confirming the cytotoxic effect of Gemini-Cur by MTT and apoptotic assays, RNA sequencing was employed to identify differentially expressed genes (DEGs) in HCT-116 cells. On a total of 3892 DEGs (padj < 0.01), 442 genes showed a log2 FC >|2| (including 244 upregulated and 198 downregulated). Gene ontology (GO) enrichment analysis was performed. Protein–protein interaction (PPI) and gene-pathway networks were constructed by using STRING and Cytoscape. The pathway analysis showed that Gemini-Cur predominantly modulates pathways related to the cell cycle. The gene network analysis revealed five central genes, namely GADD45G, ATF3, BUB1B, CCNA2 and CDK1. Real-time PCR and Western blotting analysis confirmed the significant modulation of these genes in Gemini-Cur-treated compared to non-treated cells. In conclusion, RNA sequencing revealed novel potential targets of curcumin on cancer cells. Further studies are required to elucidate the molecular mechanism of action of Gemini-Cur regarding the modulation of the expression of hub genes.
Background: Gemini Curcumin (Gemini-Cur) is the latest nano formulation of curcumin with a significant apoptotic effect on cancer cell lines. Objective: This in vitro study aims to evaluate the apoptotic effects of Gemini-Cur toward MDA-MB-468 breast cancer cell lines and further the related mechanism of apoptosis. Methods: The cytotoxicity of Gemini-Cur toward MDA-MB-468 cell lines was tested using MTT assay. Furthermore, the expression ratio of Bax/Bcl-2 was evaluated by qRT-PCR. Consequently, the protein expression of Bax/Bcl-2, survivin, and caspase-3 was measured using western blotting. Results: Having treated MDA-MB-468 cell lines with Gemini-Cur, the IC50 values were found to be 44.44 and 31.63 µM at 24 and 48 h, respectively. Our findings showed that Gemini-Cur significantly suppresses cancerous cell proliferation in a time- and dose-dependent manner. Furthermore, the data revealed that curcumin nanoformulation induces apoptosis in MDA-MB-468 cells through modulation of the expression of Bax, Bcl-2, Survivin, and Caspase-3. Conclusion: The data of the current study propose that Gemini-Cur can be considered a promising candidate against triple-negative breast cancer.
Triple Negative Breast Cancer (TNBC) is the aggressive and lethal type of breast malignancy that develops resistance to current therapies. Combination therapy has proven to be an effective strategy on TNBC. We aimed to study whether the nano-formulation of polyphenolic curcumin (Gemini-Cur) would affect the cisplatin-induced toxicity in MDA-MB-231 breast cancer cells. MDA-MB-231 cells were treated with Gemini-Cur, cisplatin and combination of Gemini-Cur/Cisplatin in a time- and dose-dependent manner. Cell viability was studied by using MTT, fluorescence microscopy and cell cycle assays. The mode of death was also determined by Hoechst staining and annexin V-FITC. Real-time PCR and western blotting were employed to detect the expression of BAX and BCL-2 genes. Our data demonstrated that Gemini-Cur significantly sensitizes cancer cells to cisplatin (combination index ≤ 1) and decreases IC50 values in comparison with Gemini-cur or cisplatin. Further studies confirmed that Gemini-Cur/Cisplatin suppresses cancer cell growth through induction of apoptosis (p < 0.001). In conclusion, the data confirm the synergistic effect of polyphenolic curcumin on cisplatin toxicity and provide attractive strategy to attain its apoptotic effect on TNBC.
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