Editor: Sarah
Ovarian cancer continues to be one of the most lethal cancers in women, primarily due to late-stage diagnoses and the development of resistance to conventional chemotherapy treatments. A recent study has explored the combination of dendrosomal nanocurcumin (DNC), a formulation of curcumin with enhanced bioavailability, and oxaliplatin (Oxa), a commonly used chemotherapy drug. The study investigates whether the combination of these two agents could offer more effective treatment options for ovarian cancer, potentially overcoming the challenges of chemotherapy resistance while minimizing side effects.
The study, published in Biological Research in 2023, focuses on the combined effects of DNC and Oxa on ovarian cancer cells, particularly in two aggressive cell lines, SKOV3 and OVCAR3. The results suggest that the synergy between these agents could provide a more effective approach to treating ovarian cancer, which is known for its rapid spread and resistance to conventional treatments.
Previous Research and Study’s Contribution
Curcumin has long been known for its anticancer properties, including its ability to induce cell death (apoptosis), block cell cycle progression, and prevent metastasis. However, its clinical application has been limited by poor bioavailability. To address this, DNC was developed as a dendrosomal formulation to enhance the bioavailability and effectiveness of curcumin. In contrast, oxaliplatin is a platinum-based chemotherapy agent used in ovarian cancer treatment, but its efficacy is often limited by the development of resistance and severe side effects.
This study’s contribution lies in investigating the combination of DNC and Oxa. The research highlights that when used together, these agents enhance each other’s effectiveness in reducing cancer cell proliferation, motility, invasion, and adhesion. Additionally, the combination significantly reduced the expression of matrix metalloproteinases (MMP-2 and MMP-9), proteins that play a key role in the metastatic process, more effectively than either treatment alone.
Contributions and Key Findings
Reduction in Cancer Cell Motility, Invasion, and Adhesion:
The study demonstrated that the combination of DNC and Oxa reduced cell motility, invasion, and adhesion in both SKOV3 and OVCAR3 ovarian cancer cell lines.
These processes are crucial for the metastasis of cancer, and their inhibition is essential for effective cancer treatment.
Synergistic Downregulation of MMP-2 and MMP-9:
MMP-2 and MMP-9 are matrix metalloproteinases involved in the degradation of the extracellular matrix (ECM), facilitating the spread of cancer cells. The combination of DNC and Oxa was found to significantly downregulate the expression of these proteins compared to single-agent treatments.
This reduction in MMP expression suggests that the combination therapy could effectively limit ovarian cancer’s ability to metastasize.
Figure 2: Docking of Oxaliplatin (Oxa) with MMP-2.
Induction of Apoptosis:
The combination treatment of DNC and Oxa led to a significant increase in apoptosis, as indicated by the accumulation of cells in the sub-G0 phase of the cell cycle, which is associated with cell death.
This shift was more pronounced when both agents were used together, highlighting the potential of the combination to induce cell death more effectively than either agent alone.
Figure 3: Docking of Dendrosomal Nanocurcumin (DNC) with MMP-2.
Molecular Dynamics and Docking Simulations:
The researchers used molecular dynamics simulations to explore how DNC, Oxa, and MMP-2 interact at a molecular level. The results indicated that both DNC and Oxa formed strong bonds with MMP-2, further supporting the hypothesis that these agents could inhibit the metastatic process.
Docking results also identified specific residues of MMP-2, such as His70 and Asp100, which interact with the drugs, potentially blocking their activity and inhibiting cancer cell spread.
Figure 4: Docking of Curcumin with MMP-2.
Inhibition of Colony Formation:
The colony formation assay demonstrated that the combination of DNC and Oxa significantly decreased the ability of both SKOV3 and OVCAR3 cells to form colonies, a key indicator of cancer cell proliferation and survival.
The combination treatment was more effective than either single agent, showing its potential in reducing the long-term survival of cancer cells.
Figure 1: Effect of DNC, Oxa, and Combination on Colony Formation in OVCAR3 and SKOV3 Cells.
Impact on Cell Cycle:
The study further analyzed the effect of DNC and Oxa on the cell cycle. The combination treatment resulted in a significant reduction in the G2/M phase of the cell cycle and an increased accumulation of cells in the sub-G0 phase, suggesting a higher rate of apoptosis.
This finding supports the idea that the combination therapy may not only reduce proliferation but also increase the sensitivity of ovarian cancer cells to treatment.
Changes in Gene Expression:
Real-time PCR analysis revealed that the combination treatment significantly affected the mRNA expression levels of genes involved in key signaling pathways, including AKT, PI3K, MAPK, and MMPs.
The combination therapy more effectively downregulated the expression of MMP-2 and MMP-9 compared to single-agent treatments, emphasizing its potential to alter the molecular environment of cancer cells in favor of tumor suppression.
Methodology
The study utilized a variety of in vitro assays to assess the effects of DNC, Oxa, and their combination on ovarian cancer cell lines:
- Colony Formation Assay: Used to evaluate the long-term survival of cancer cells after treatment.
- Wound Healing Assay: Assessed cell motility by measuring the rate of cell migration into a wound gap created in a cell monolayer.
- Cell Adhesion and Invasion Assays: Measured the ability of cancer cells to adhere to extracellular matrices and invade through barriers.
- Flow Cytometry: Analyzed cell cycle distribution to assess the effect of treatments on cell proliferation and apoptosis.
- Molecular Dynamics Simulations: Investigated the interaction between DNC, Oxa, and MMP-2 at a molecular level.
Figure 5: Molecular Dynamics Simulations of Complexes (RMSD and RMSF).
Implications and Applications
The findings from this study have important implications for the treatment of ovarian cancer. The combination of DNC and Oxa could potentially overcome the limitations associated with each individual treatment. By reducing resistance to Oxa and minimizing its side effects, this combination could offer a more viable long-term treatment option for ovarian cancer patients.
Additionally, this synergistic approach could be applied to other cancers that exhibit similar metastatic behaviors. The use of molecular dynamics simulations could also inform the development of new treatments by providing insights into the interactions between drugs and target proteins.
Conclusion
In conclusion, this study provides valuable insights into the potential of combining dendrosomal nanocurcumin and oxaliplatin as a treatment strategy for ovarian cancer. The results suggest that this combination could significantly reduce cancer cell motility, invasion, and metastasis, while enhancing cell death induction. While these preclinical findings are promising, further clinical studies are necessary to evaluate the safety and efficacy of this combination therapy in human patients.
Reference
Seyed Hosseini, Elahe, et al. “Synergistic Effects of Dendrosomal Nanocurcumin and Oxaliplatin on Oncogenic Properties of Ovarian Cancer Cell Lines by Down-Expression of MMPs.” Biological Research, vol. 56, no. 3, 2023, https://doi.org/10.1186/s40659-023-00412-x.