Abstract
BackgroundChemo/radio-resistance is a major obstacle in treating advanced ovarian cancer. The efficacy of current treatments may be improved by increasing the sensitivity of cancer cells to chemo/radiation therapies. Curcumin is a naturally occurring compound with anti-cancer activity in multiple cancers; however, its chemo/radio-sensitizing potential is not well studied in ovarian cancer. Herein, we demonstrate the effectiveness of a curcumin pre-treatment strategy for chemo/radio-sensitizing cisplatin resistant ovarian cancer cells. To improve the efficacy and specificity of curcumin induced chemo/radio sensitization, we developed a curcumin nanoparticle formulation conjugated with a monoclonal antibody specific for cancer cells.MethodsCisplatin resistant A2780CP ovarian cancer cells were pre-treated with curcumin followed by exposure to cisplatin or radiation and the effect on cell growth was determined by MTS and colony formation assays. The effect of curcumin pre-treatment on the expression of apoptosis related proteins and β-catenin was determined by Western blotting or Flow Cytometry. A luciferase reporter assay was used to determine the effect of curcumin on β-catenin transcription activity. The poly(lactic acid-co-glycolic acid) (PLGA) nanoparticle formulation of curcumin (Nano-CUR) was developed by a modified nano-precipitation method and physico-chemical characterization was performed by transmission electron microscopy and dynamic light scattering methods.ResultsCurcumin pre-treatment considerably reduced the dose of cisplatin and radiation required to inhibit the growth of cisplatin resistant ovarian cancer cells. During the 6 hr pre-treatment, curcumin down regulated the expression of Bcl-XL and Mcl-1 pro-survival proteins. Curcumin pre-treatment followed by exposure to low doses of cisplatin increased apoptosis as indicated by annexin V staining and cleavage of caspase 9 and PARP. Additionally, curcumin pre-treatment lowered β-catenin expression and transcriptional activity. Nano-CUR was successfully generated and physico-chemical characterization of Nano-CUR indicated an average particle size of ~70 nm, steady and prolonged release of curcumin, antibody conjugation capability and effective inhibition of ovarian cancer cell growth.ConclusionCurcumin pre-treatment enhances chemo/radio-sensitization in A2780CP ovarian cancer cells through multiple molecular mechanisms. Therefore, curcumin pre-treatment may effectively improve ovarian cancer therapeutics. A targeted PLGA nanoparticle formulation of curcumin is feasible and may improve the in vivo therapeutic efficacy of curcumin.
Highlights
IntroductionThe efficacy of current treatments may be improved by increasing the sensitivity of cancer cells to chemo/radiation therapies
Chemo/radio-resistance is a major obstacle in treating advanced ovarian cancer
Pre-treatment with 20 μM curcumin for 6 hrs followed by treatment with 2.5-40 μM cisplatin for an additional 42 hrs resulted in drastic cell growth inhibition compared to each agent alone (Figure 1B, CUR + CIS)
Summary
The efficacy of current treatments may be improved by increasing the sensitivity of cancer cells to chemo/radiation therapies. We demonstrate the effectiveness of a curcumin pre-treatment strategy for chemo/radio-sensitizing cisplatin resistant ovarian cancer cells. Nation of platinum (cisplatin or carboplatin) and taxane based therapies This is effective in 60-80% of patients; the majority of women with advanced disease will have cancer recurrence [2,3]. Independent of the mechanism of resistance, inhibition of cell death via apoptosis is an important event leading to cisplatin resistance Another important aspect limiting the use of cisplatin is the negative side effects which accumulate in severity with multiple cisplatin treatments and include gastrointestinal distress, kidney and nerve damage, hearing loss, and bone marrow suppression [2,3,6]. While significant progress has been made in developing targeted radioimmunotherapy (RIT), current drawbacks to this therapy include toxicity and resistance to radiation [7,8]
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