Curcumin induces chemo/radio-sensitization in ovarian cancer cells and curcumin nanoparticles inhibit ovarian cancer cell growth

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.

Polyphenols delivery by polymeric materials: challenges in cancer treatment

“…The association with CP is also useful for ovarian cancer treatment (Yallapu et al, 2010b), while in vivo studies proved the synergism of CUR nanoformulation prepared by free radical polymerization of NIPAAm, VP, and AA with Gemcitabine in Pa03C Xenograft mouse model (Bisht et al, 2010).…”

“…CUR nanocarriers have been also proposed for the treatment of breast cancer in combination therapy with conventional cytotoxic agents such as 5-FU (Balasubramanian et al, 2014), Doxorubicin (DOX) (Duan et al, 2012), and CP (Yallapu et al, 2010b) with synergistic activity. The association with CP is also useful for ovarian cancer treatment (Yallapu et al, 2010b), while in vivo studies proved the synergism of CUR nanoformulation prepared by free radical polymerization of NIPAAm, VP, and AA with Gemcitabine in Pa03C Xenograft mouse model (Bisht et al, 2010).…”

The Pleiotropic Effects of Curcumin.

“…In the same experiment these curcumin pretreated cells exposed to radiation exhibited more suppression of colony formation than either agent (curcumin or radiation) alone [16] .…”

“…The pleiotropic effects of curcumin can be summarised in the following [6] apoptosis by induction of caspase activity (demethoxycurcumin) [10] Mcl-1 downregulation [12] Radiosensitisation [15] Chemosensitisation [16] Diabetes/metabolic syndrome Improve insulin sensitivity [17] increases the levels of anti inflammatory cytokines like adiponectin [19,20] improved endothelial function [21] decrease in inflammatory cytokines and oxidative stress markers [21] Skin diseases decreases IL-22 levels [23] Osteoarthritis (Curcuma domestica) apoptosis of synovial adherent cells. [30] Neuroprotection Alzheimer disease(in vitro)…”

“…In another study done on ovarian cancer cells which were resistant to cisplatin, pretreatment with curcumin produced higher inhibition of cancer cell proliferation than either curcumin or cisplatin given alone and also produced an appreciable decline in the required cisplatin dose, demonstrating its chemosensitising action [16] . In the same experiment these curcumin pretreated cells exposed to radiation exhibited more suppression of colony formation than either agent (curcumin or radiation) alone [16] .…”