Curcumin derivative ST09 modulates the miR-199a-5p/DDR1 axis and regulates proliferation and migration in ovarian cancer cells

Ovarian cancers are among the fatal malignancies affecting women globally, mainly due to their metastatic and chemoresistant nature. In this study, we report a potent curcumin derivative ST09 effective against ovarian cancers. Prior in-vitro studies with ST09 drug showed cytotoxicity in tumorigenic cells compared to normal cells and in-vivo, significant tumor reduction was observed with least systemic toxicity. ST09 induced cytotoxicity in the ovarian cancer cells triggering mitochondria-mediated intrinsic apoptotic pathway. Delving deeper to understand the underlying molecular mechanisms involved in ovarian cancer pathogenesis, we identified an inverse correlation of miR-199a-5p with DDR1, a collagen receptor with receptor tyrosine kinase activity. The ST09 treatment in ovarian cancer cell lines resulted in the deregulation of the miR-199a-5p/DDR1 axis, conferring tumor-suppressive functions. We established DDR1 to be a direct target of miR-199a-5p and that ST09-induced DDR1 loss in these ovarian cancer cells resulted in the inactivation of its downstream MMP activation, migration, EMT, and prosurvival NF-κB pathway. Overall this study demonstrates ST09, a potent drug candidate for ovarian cancer treatment which exhibits anti-invasive and migrastatic properties.

Toxicity, Pharmacokinetics, And Antitumor Activity Study of a Novel Long-Acting Paclitaxel Nanodrug Delivery System Constructed On a Curcumin Derivative Carrier

Purpose/Background: Paclitaxel (PTX) has been widely used in the clinic to treat breast cancer. However, its poor water solubility and intolerable toxicity greatly reduce the efficacy and medication safety. In this paper, a curcumin derivative (CUD) synthesized by the research group was used as a carrier to prepare a new type of PTX nanodrug delivery system (CUD-PTX-LN), thereby improving the safety of PTX medication and enhancing the anti-tumor effect.Methods: CUD-PTX-LN was prepared by solid dispersion technology and the dialysis method was adopted to investigate the release behavior of CUD-PTX-LN in vitro. Meanwhile, the dynamic process of nanoparticles in vivo was analyzed by pharmacokinetic experiments. Hemolysis experiment, acute toxicity and cumulative toxicity were conducted in mice to evaluate the safety of CUD-PTX-LN. Subsequently, the anti-tumor activity of CUD-PTX-LN was investigated using in vitro and in vivo breast cancer cell models.Results: The average particle size, PDI, and Zeta potential of CUD-PTX-LN were 238.5 ± 4.79 nm, 0.225 ± 0.011 and -33.8 ± 1.26 mV, respectively. CUD-PTX-LN had an encapsulation efficiency (%EE) of 94.20 ± 0.49% and an achievable drug loading (%DL) of 10.98 ± 0.31%. This nanoparticle was stable for up to half a year when the lyophilized powder was stored at room temperature. Cytotoxicity test on MCF-7 cells demonstrated the stronger cytotoxic activity of nanoparticles in comparison to free PTX. CUD-PTX-LN significantly prolonged the half-life and retention time of PTX. The area under the curve (AUC) of CUD-PTX-LN was 14.72 mg/L × h, which was 6 times that of the free PTX group (2.38 mg/L × h). In anti-tumor experiments in vivo, CUD-PTX-LN possessed the advantages of improving the antitumor efficacy and reducing the toxic side effects of drugs. Importantly, CUD-PTX-LN is safer than free PTX in terms of assessing hemolytic, acute and cumulative toxicity.Conclusion: A novel PTX nanodrug delivery system constructed based on CUD as a carrier holds great potential in improving breast cancer treatment.

Curcumin Derivatives as Potential Mosquito Larvicidal Agents against Two Mosquito Vectors, Culex pipiens and Aedes albopictus

Vector-borne diseases have appeared or re-emerged in many Southern Europe countries making the transmission of infectious diseases by mosquitoes (vectors) one of the greatest worldwide health threats. Larvicides have been used extensively for the control of Aedes (Stegomyia) albopictus (Skuse, 1895) (Diptera: Culicidae) and Culex pipiens Linnaeus, 1758 (Diptera: Culicidae) mosquitoes in urban and semi-urban environments, causing the increasing resistance of mosquitoes to commercial insecticides. In this study, 27 curcuminoids and monocarbonyl curcumin derivatives were synthesised and evaluated as potential larvicidal agents against Cx. pipiens and Ae. albopictus. Most of the compounds were more effective against larvae of both mosquito species. Four of the tested compounds, curcumin, demethoxycurcumin, curcumin-BF2 complex and a monocarbonyl tetramethoxy curcumin derivative exhibited high activity against both species. In Cx. pipiens the recorded LC50 values were 6.0, 9.4, 5.0 and 32.5 ppm, respectively, whereas in Ae. albopictus they exhibited LC50 values of 9.2, 36.0, 5.5 and 23.6 ppm, respectively. No conclusive structure activity relationship was evident from the results and the variety of descriptors values generated in silico provided some insight to this end.

Polysaccharide Matrices for the Encapsulation of Tetrahydrocurcumin—Potential Application as Biopesticide against Fusarium graminearum

Cereals are subject to contamination by pathogenic fungi, which damage grains and threaten public health with their mycotoxins. Fusarium graminearum and its mycotoxins, trichothecenes B (TCTBs), are especially targeted in this study. Recently, the increased public and political awareness concerning environmental issues tends to limit the use of traditional fungicides against these pathogens in favor of eco-friendlier alternatives. This study focuses on the development of biofungicides based on the encapsulation of a curcumin derivative, tetrahydrocurcumin (THC), in polysaccharide matrices. Starch octenylsuccinate (OSA-starch) and chitosan have been chosen since they are generally recognized as safe. THC has been successfully trapped into particles obtained through a spray-drying or freeze-drying processes. The particles present different properties, as revealed by visual observations and scanning electron microscopy. They are also different in terms of the amount and the release of encapsulated THC. Although freeze-dried OSA-starch has better trapped THC, it seems less able to protect the phenolic compound than spray-dried particles. Chitosan particles, both spray-dried and lyophilized, have shown promising antifungal properties. The IC50 of THC-loaded spray-dried chitosan particles is as low as 0.6 ± 0.3 g/L. These particles have also significantly decreased the accumulation of TCTBs by 39%.

The Novel Curcumin Derivative 1g Induces Mitochondrial and ER-Stress-Dependent Apoptosis in Colon Cancer Cells by Induction of ROS Production

Reactive oxygen species (ROS) play an important role in cellular metabolism. Many chemotherapeutic drugs are known to promote apoptosis through the production of ROS. In the present study, the novel curcumin derivative, 1g, was found to inhibit tumor growth in colon cancer cells both in vitro and in vivo. Bioinformatics was used to analyze the differentially expressed mRNAs. The mechanism of this effect was a change in mitochondrial membrane potential caused by 1g that increased its pro-apoptotic activity. In addition, 1g produced ROS, induced G1 checkpoint blockade, and enhanced endoplasmic reticulum (ER)-stress in colon cancer cells. Conversely, pretreatment with the ROS scavenging agent N-acetyl-l-cysteine (NAC) inhibited the mitochondrial dysfunction caused by 1g and reversed ER-stress, cell cycle stagnation, and apoptosis. Additionally, pretreatment with the p-PERK inhibitor GSK2606414 significantly reduced ER-stress and reversed the apoptosis induced by colon cancer cells. In summary, the production of ROS plays an important role in the destruction of colon cancer cells by 1g and demonstrates that targeted strategies based on ROS represent a promising approach to inhibit colon cancer proliferation. These findings reveal that the novel curcumin derivative 1g represents a potential candidate therapeutics for the treatment of colon cancer cells, via apoptosis caused by mitochondrial dysfunction and endoplasmic reticulum stress.