The Beneficial Effects of Combining Anti-Aβ Antibody NP106 and Curcumin Analog TML-6 on the Treatment of Alzheimer’s Disease in APP/PS1 Mice

Alzheimer’s disease (AD) is a progressive neurodegenerative disease with a multifactorial etiology. A multitarget treatment that modulates multifaceted biological functions might be more effective than a single-target approach. Here, the therapeutic efficacy of combination treatment using anti-Aβ antibody NP106 and curcumin analog TML-6 versus monotherapy was investigated in an APP/PS1 mouse model of AD. Our data demonstrate that both combination treatment and monotherapy attenuated brain Aβ and improved the nesting behavioral deficit to varying degrees. Importantly, the combination treatment group had the lowest Aβ levels, and insoluble forms of Aβ were reduced most effectively. The nesting performance of APP/PS1 mice receiving combination treatment was better than that of other APP/PS1 groups. Further findings indicate that enhanced microglial Aβ phagocytosis and lower levels of proinflammatory cytokines were concurrent with the aforementioned effects of NP106 in combination with TML-6. Intriguingly, combination treatment also normalized the gut microbiota of APP/PS1 mice to levels resembling the wild-type control. Taken together, combination treatment outperformed NP106 or TML-6 monotherapy in ameliorating Aβ pathology and the nesting behavioral deficit in APP/PS1 mice. The superior effect might result from a more potent modulation of microglial function, cerebral inflammation, and the gut microbiota. This innovative treatment paradigm confers a new avenue to develop more efficacious AD treatments.

The curcumin analog EF24 inhibits proliferation and invasion of triple-negative breast cancer cells by targeting the lncRNA HCG11/Sp1 axis

EF24, a curcumin analog, exerts a potent anti-tumor effect on various cancers. However, whether EF24 retards the progression of triple-negative breast cancer (TNBC) remains unclear. In this study, we explored the role of EF24 in TNBC and clarified the underlying mechanism. In a mouse model of TNBC xenograft, EF24 administration reduced the tumor volume, suppressed cell proliferation, promoted cell apoptosis, and downregulated long non-coding RNA human leukocyte antigen complex group 11 (HCG11) expression. In TNBC cell lines, EF24 administration reduced cell viability, suppressed cell invasion, and downregulated HCG11 expression. HCG11 overexpression re-enhanced the proliferation and invasion of TNBC cell lines suppressed by EF24. The following mechanism research revealed that HCG11 overexpression elevated Sp1 transcription factor (Sp1) expression by reducing its ubiquitination, thereby enhanced Sp1-mediated cell survival and invasion in the TNBC cell line. Finally, the in vivo study showed that HCG11-overexpressed TNBC xenografts exhibited lower responsiveness in response to EF24 treatment. In conclusion, EF24 treatment reduced HCG11 expression, resulting in the degradation of Sp1 expression, thereby inhibiting the proliferation and invasion of TNBC cells.

The Synthetic Curcumin Analog HO-3867 Rescues Suppression of PLAC1 Expression in Ovarian Cancer Cells

Elevated expression of placenta-specific protein 1 (PLAC1) is associated with the increased proliferation and invasiveness of a variety of human cancers, including ovarian cancer. Recent studies have shown that the tumor suppressor p53 directly suppresses PLAC1 transcription. However, mutations in p53 lead to the loss of PLAC1 transcriptional suppression. Small molecules that structurally convert mutant p53 proteins to wild-type conformations are emerging. Our objective was to determine whether the restoration of the wild-type function of mutated p53 could rescue PLAC1 transcriptional suppression in tumors harboring certain TP53 mutations. Ovarian cancer cells OVCAR3 and ES-2, both harboring TP53 missense mutations, were treated with the p53 reactivator HO-3867. Treatment with HO-3867 successfully rescued PLAC1 transcriptional suppression. In addition, cell proliferation was inhibited and cell death through apoptosis was increased in both cell lines. We conclude that the use of HO-3867 as an adjuvant to conventional therapeutics in ovarian cancers harboring TP53 missense mutations could improve patient outcomes. Validation of this conclusion must, however, come from an appropriately designed clinical trial.

Curcumin Analogs, PGV-1 and CCA-1.1 Exhibit Anti-migratory Effects and Suppress MMP9 Expression on WiDr Cells

BACKGROUND: Colon cancer is still a crucial concern in the development of chemotherapeutic drugs due to the drug resistance phenomenon and various side effects to patients. One of the newest compound that show anticancer activities against several cancer cells, Chemoprevention Curcumin Analog 1 (CCA-1.1), has increasingly been explored to overcome the limitation of conventional drugs.METHODS: We evaluated the anti-migratory effect of CCA-1.1 and Pentagamavunone-1 (PGV-1) by using WiDr colon cancer cells. The expression profiles of Tumor Protein 53 (TP53) and Matrix Metalloproteinase-9 (MMP9) in colon cancer were obtained from the UALCAN database. Survival outcomes of TP53 and MMP9 in colon cancer patients were analyzed using the Kaplan-Meier method. We used 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT), scratch wound healing, and gelatin zymography assays to observe the cytotoxic effect, anti-migratory activity, and MMP9 expression, respectively, in CCA-1.1 or PGV-1-treated cells.RESULTS: Level of MMP9 was found significantly overexpressed in the primary tumor and metastasis nodal, while TP53 mutation sample types were observed and influenced the survival outcome in colon cancer patients. CCA-1.1 and PGV-1 exhibited strong cytotoxic activity after 24 and 48 h treatment against WiDr cells. The migration assay demonstrated that PGV-1 and CCA-1.1 at 1 mM inhibited cell migration up to 40% after 48 h in single and combination with doxorubicin. The MMP9 expression was significantly inhibited by 0.5 mM CCA-1.1.CONCLUSION: This study emphasizes that the anti-migratory effect of CCA-1.1 is better than PGV-1 via MMP9 suppression on WiDr. Thus, CCA-1.1 is prominent to be developed as an anti-metastatic agent.KEYWORDS: chemopreventive curcumin analog 1.1 (CCA-1.1), PGV-1, WiDr cells, anti-migration, MMP9

2-Chloro-4,6-bis{(E)-3-methoxy-4-[(4-methoxybenzyl)oxy]styryl}pyrimidine: Synthesis, Spectroscopic and Computational Evaluation

A novel curcumin analog namely 2-chloro-4,6-bis{(E)-3-methoxy-4-[(4-methoxybenzyl)oxy]-styryl}pyrimidine (compound 7) was synthesized by three-step reaction. The condensation reaction of protected vanillin with 2-chloro-4,6-dimethylpyrimidine (6) was the most efficient step, resulting in a total yield of 72%. The characterization of compound 7 was performed by 1H and 13C nuclear magnetic resonance (NMR), as well as high-resolution mass spectrometry. The experimental spectrometric data were compared with the theoretical spectra obtained by the density functional theory (DFT) method, showing a perfect match between them. UV-visible spectroscopy and steady-state fluorescence emission studies were performed for compound 7 in solvents of different polarities and the results were correlated with DFT calculations. Compound 7 showed a solvatochromism effect presenting higher molar extinction coefficient (log ε = 4.57) and fluorescence quantum yield (ϕ = 0.38) in toluene than in acetonitrile or methanol. The simulation of both frontier molecular orbitals (FMOs) and molecular electrostatic potential (MEP) suggested that the experimental spectra profile in toluene was not interfered by a possible charge transfer. These results are an indication of a low probability of compound 7 in reacting with unsaturated phospholipids in future applications as a fluorescent dye in biological systems.

Preparation and Cytotoxic Evaluation of PGV-1 Derivative, CCA-1.1, as a New Curcumin Analog with Improved-Physicochemical and Pharmacological Properties

Purpose: This study aimed to challenge the anticancer potency of PGV-1 and obtain a new compound (Chemoprevention-Curcumin Analog 1.1, CCA-1.1) with improved chemical and pharmacological properties. Methods: CCA-1.1 was prepared by changing the ketone group of PGV-1 into a hydroxyl group with NaBH4 as the reducing agent. The product was purified under preparative layer chromatography and confirmed with HPLC to show about 98% purity. It was tested for its solubility, stability, and cytotoxic activities on several cancer cells. The structure of the product was characterized using 1HNMR, 13C-NMR, FT-IR, and HR-mass spectroscopy. Results: Molecular docking analysis showed that CCA-1.1 performed similar or better interaction to NF-kB pathway-related signaling proteins (HER2, EGFR, IKK, ER-alpha, and ER-beta) and reactive oxygen species metabolic enzymes (NQO1, NQO2, GSTP1, AKC1R1, and GLO1) compared with PGV-1, indicating that CCA-1.1 exhibits the same or better anticancer activity than PGV-1. CCA-1.1 also showed better solubility and stability than PGV-1 in aqueous solution at pH 1.0–7.4 under light exposure at room temperature. The cytotoxic activities of CCA-1.1 against several (10) cancer cell lines revealed the same or better potency than PGV-1. Conclusion: In conclusion, CCA-1.1 performs better chemical and anticancer properties than PGV-1 and shows promise as an anticancer agent with high selectivity.