A radiosensitizer, gallotannin-rich extract from Bouea macrophylla seeds, inhibits radiation-induced epithelial-mesenchymal transition in breast cancer cells

Abstract

Background Radioresistance can pose a significant obstacle to the effective treatment of breast cancers. Epithelial–mesenchymal transition (EMT) is a critical step in the acquisition of stem cell traits and radioresistance. Here, we investigated whether Maprang seed extract (MPSE), a gallotannin-rich extract of seed from Bouea macrophylla Griffith, could inhibit the radiation-induced EMT process and enhance the radiosensitivity of breast cancer cells. Methods Breast cancer cells were pre-treated with MPSE before irradiation (IR), the radiosensitizing activity of MPSE was assessed using the colony formation assay. Radiation-induced EMT and stemness phenotype were identified using breast cancer stem cells (CSCs) marker (CD24−/low/CD44+) and mammosphere formation assay. Cell motility was determined via the wound healing assay and transwell migration. Radiation-induced cell death was assessed via the apoptosis assay and SA-β-galactosidase staining for cellular senescence. CSCs- and EMT-related genes were confirmed by real-time PCR (qPCR) and Western blotting. Results Pre-treated with MPSE before irradiation could reduce the clonogenic activity and enhance radiosensitivity of breast cancer cell lines with sensitization enhancement ratios (SERs) of 2.33 and 1.35 for MCF7 and MDA-MB231cells, respectively. Pretreatment of breast cancer cells followed by IR resulted in an increased level of DNA damage maker (γ-H2A histone family member) and enhanced radiation-induced cell death. Irradiation induced EMT process, which displayed a significant EMT phenotype with a down-regulated epithelial marker E-cadherin and up-regulated mesenchymal marker vimentin in comparison with untreated breast cancer cells. Notably, we observed that pretreatment with MPSE attenuated the radiation-induced EMT process and decrease some stemness-like properties characterized by mammosphere formation and the CSC marker. Furthermore, pretreatment with MPSE attenuated the radiation-induced activation of the pro-survival pathway by decrease the expression of phosphorylation of ERK and AKT and sensitized breast cancer cells to radiation. Conclusion MPSE enhanced the radiosensitivity of breast cancer cells by enhancing IR-induced DNA damage and cell death, and attenuating the IR-induced EMT process and stemness phenotype via targeting survival pathways PI3K/AKT and MAPK in irradiated breast cancer cells. Our findings describe a novel strategy for increasing the efficacy of radiotherapy for breast cancer patients using a safer and low-cost natural product, MPSE.

Gallotannin from Bouea macrophylla Seed Extract Suppresses Cancer Stem-like Cells and Radiosensitizes Head and Neck Cancer

“…We have recently demonstrated that MPSE possessed promising anti-cancer activity and radiosensitization in breast cancer cells by inhibiting IR-induced pro-survival signaling [19]. This study extends this observation to HNSCC, where poor patient prognosis and treatment failure were found due to intrinsic tumor radioresistance in HNSCC.…”

“…The reduced activation of STAT3 results in the downregulation of downstream target Bcl-XL and Mcl-1 and further induced apoptosis [18]. A notable recent report by our team showed that MPSE pretreatment before irradiation in breast cancer cells inhibits the radiation induced epithelial to mesenchymal transition (EMT) process and confers radiosensitivity, probably by attenuating the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) and mitogen-activated protein kinase (MAPK) pathways [19].…”

The Evolution of Pharmacological Activities Bouea macrophylla Griffith In Vivo and In Vitro Study: A Review

“…Before irradiation, pretreatment of MCF-7 with plum mango seed extract (MPSE) affected the chemoresistance (MCF-7/MPIR6). MCF-7/MPIR6 cells decreased Pgp (ABCB1) mRNA expression but still expressed MRP1 and BCRP mRNA similar to parent MCF7 [27]. This shows that pretreatment with MPSE is able to prevent drug resistance (chemoresistance) by reducing the expression of the ABCB1 gene associated with the drug efflux pump (P-gp).…”

“…This shows that the combination of MPSE therapy with IR can increase the radiosensitivity of breast cancer cells and increase radiation-induced DNA damage. This combination therapy also increases apoptosis higher than IR therapy alone [27]. MCF-7/FIR is breast cancer cells that survive after radiation, have potential as malignant cells characterized by a high migration rate compared to MCF-7 parent cells [24].…”

“…They are reported to have various pharmacological activities such as antioxidant, antimicrobial, anticancer, and antihyperglycemic [10][11][12][13][14]. Related to these data, plum mango has been reported to have various pharmacological activities, including antioxidant [2,3,[15][16][17][18][19][20][21][22], anticancer [3,[23][24][25][26][27], antimicrobial [3,28,29], antihyperglycemic [15,16,20,30], antiphotoaging [30], and can increase vegetable intake and increase the concentration of beta carotene in the blood [31]. By virtue of the use of B. macrophylla Griffith as a herbal medicine and the lack of widespread use of this plant due to the limited information about its therapeutic benefits and compound content, we present this review of the pharmacological activities of B. macrophylla Griffith.…”