Synergistic effects of dendrosomal nanocurcumin and oxaliplatin on oncogenic properties of ovarian cancer cell lines by down-expression of MMPs

Abstract

Background Contrary to the advantageous anticancer activities of curcumin (Cur), limited bioavailability and solubility hindered its efficacy. Here, nontoxic dendrosomal nano carrier with Cur was used to overcome these problems. Despite considerable antitumor properties of Oxaliplatin (Oxa), the limiting factors are drug resistance and adverse side-effects. The hypothesis of this study was to evaluate the possible synergism between dendrosomal nanocurcumin (DNC) and Oxa and these agents showed growth regulatory effects on SKOV3 and OVCAR3 cells. Methods and materials In the present study, colony formation, wound healing motility, cell adhesion, transwell invasion and migration assay and cell cycle arrest with or without DNC, Oxa and Combination were defined. In addition to, real time PCR and Western blot were used to analyze AKT, PI3K, PKC, JNK, P38 and MMPs mRNAs and proteins expressions. Docking of MMP-2-Cur, MMP-2-DNC and MMP-2-Oxa was performed and the results of all three complexes were simulated by molecular dynamics. Results Our findings illustrated that DNC had the greatest effect on cell death as compared to the Cur alone. Moreover, the growth inhibitory effects (such as cell death correlated to apoptosis) were more intense if Oxa was added followed by DNC at 4 h interval. However, insignificant effects were observed upon simultaneous addition of these two agents in both cell lines. Besides, a combination of agents synergistically alters the relative expression of MMP-9. Conclusions The docking results showed that His70 and Asp100 may play a key role at the MMP-2 binding site. The matrigel invasion as well as cell viability of ovarian cancer cell lines SKOV3 and OVCAR3 by DNC alone or in combination with Oxa was inhibited significantly. The inhibitory effects of these agents were due to the differential expression levels of MMP 2 and MMP 9 regulated by multiple downstream signaling cascades. From the molecular dynamic simulation studies, it was confirmed that DNC established a strong interaction with MMP-2.

Anti-Inflammatory Effects of Dietary Polyphenols through Inhibitory Activity against Metalloproteinases

“…Based on the crystallographic structure of MMP2, Hosseini et al [ 136 ] assumed that the catalytic pocket of MMP2 is composed of amino acid residues including His70, Gly81, Leu82, Leu83, His85, Ala88, Asp100, Leu116, Val117, His120, Glu121, His124, Glu129, His130, Leu137, Pro140, Ile141, Tyr142, and Try143. MDA indicated that CUR interacts with His70 and Ala86 in MMP2 through hydrogen bonding ( Figure 6 ).…”

“…MDA has provided the structural basis for the interactions between polyphenols and MMPs to understand their MMP inhibitory activity and would be useful in exploring new polyphenol-based drugs with anti-inflammatory property. An example is the finding that MDA showed that in DenCUR, a CUR derivative, oleoyl, and polyethylene glycol moieties can contribute to the increase in two hydrogen bonds to interact with the enzyme, explaining the higher biological activity of DenCUR than CUR ( Figure 6 ) [ 136 ]. A strategy to explore the modification of polyphenols that can increase MMP-interacting moieties would be useful in providing a better MMP inhibitor as an agent against inflammation-based human diseases.…”

“…Ligands are yellow, amino acids involved in the complex are purple, hydrogen bonds are green dotted lines, and side residues are red. Reprinted with permission from [ 136 ]. Copyright 2023 BioMed Central.…”

Curcumin: a natural organic component that plays a multi-faceted role in ovarian cancer

“…Finally, a curcumin-induced increase in CELF2 expression resulted in increased ovarian cancer cell sensitivity to cisplatin. Studies have shown that DNC may make ovarian cancer cells synergistically sensitize to oxaliplatin treatment by regulating proteins in MAPK pathway (including MMP-2, MMP-9, PKC, JNK, P38, PI3K and AKT) [ 88 ]. Cisplatin kills cancer cells mainly by establishing intra- and inter-strand DNA crosslinks to prevent DNA replication.…”