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

Abstract

Cancer stem cells (CSCs) play a critical role in radiation resistance and recurrence. Thus, drugs targeting CSCs can be combined with radiotherapy to improve its antitumor efficacy. Here, we investigated whether a gallotannin extract from Bouea macrophylla seed (MPSE) and its main bioactive compound, pentagalloyl glucose (PGG), could suppress the stemness trait and further confer the radiosensitivity of head and neck squamous cell carcinoma (HNSCC) cell lines. In this study, we evaluate the effect of MPSE or PGG to suppress CSC-like phenotypes and radiosensitization of HNSCC cell lines using a series of in vitro experiments, tumorsphere formation assay, colony formation assay, apoptosis assay, and Western blotting analysis. We demonstrate that MPSE or PGG is able to suppress tumorsphere formation and decrease protein expression of cancer stem cell markers. MPSE or PGG also enhanced the radiosensitivity in HNSCC cells. Pretreatment of cells with MPSE or PGG increased IR-induced DNA damage (γ-H2Ax) and enhanced radiation-induced cell death. Notably, we observed that pretreatment with MPSE or PGG attenuated the IR-induced stemness-like properties characterized by tumorsphere formation and the CD44 CSC marker. Our findings describe a novel strategy for increasing therapeutic efficacy for head and neck cancer patients using the natural products MPSE and PGG.

Pentagalloyl Glucose and Cisplatin Combination Treatment Exhibits a Synergistic Anticancer Effect in 2D and 3D Models of Head and Neck Carcinoma

“…Our previous study showed that PGG inhibited the activation of STAT3 in HPV-negative HNSCC cell lines, resulting in the suppressed self-renewal activity of cancer stem cells and inhibiting the tumor spheroid formation. Moreover, the combination treatment with PGG sensitized HPV-negative HNSCC cell lines to the effect of radiation-induced cell death, which may be at least partially mediated by the inhibition of the STAT3 pathway [ 13 ]. When activated, STAT3 is capable of mediating several critical signaling pathways, including proliferative, survival, and metastasis, and can modulate a variety of genes involved in the cell cycle (c-Myc and cyclin D1), anti-apoptosis (Bcl-2 and survivin), angiogenesis (VEGF), and metastasis (MMP-9, EMT) [ 35 ].…”

“…PGG was isolated from the seeds of Bouea macrophylla Griffith as described previously [ 13 ]. In brief, a crude ethanolic extract of Bouea macrophylla seed (MPSE) was prepared at 1 g/L in deionized water and stored at −20 °C in a freezer for 3 h, and then cooled to 4 °C by air exposure at room temperature for another 3 h. After that, the cold solution was collected and filled into a 50 mL centrifuge tube and centrifuged at 2500× g for 20 min.…”

“…Increasing evidence has suggested that plant polyphenols might be combined with conventional therapy (chemo/radiotherapy) to sensitize tumor cells to the treatment by inhibiting the pathway that leads to treatment resistance [ 9 , 10 , 11 ]. Pentagalloyl glucose (1,2,3,4,6-Penta- O -galloyl-β-D-glucose, PGG; molecular weight = 940.67 g/mol) (illustrated in Figure 1 a), a naturally occurring polyphenolic water-soluble gallotannin, is the main biologically active metabolite found, isolated, and purified in Bouea macrophylla [ 12 , 13 ]. PGG exhibits anti-cancer and anti-metastasis activity toward several types of cancer cells, including breast [ 14 , 15 ], leukemia [ 16 ], HNSCC [ 13 ], and prostate [ 17 , 18 ].…”

“…Pentagalloyl glucose (1,2,3,4,6-Penta- O -galloyl-β-D-glucose, PGG; molecular weight = 940.67 g/mol) (illustrated in Figure 1 a), a naturally occurring polyphenolic water-soluble gallotannin, is the main biologically active metabolite found, isolated, and purified in Bouea macrophylla [ 12 , 13 ]. PGG exhibits anti-cancer and anti-metastasis activity toward several types of cancer cells, including breast [ 14 , 15 ], leukemia [ 16 ], HNSCC [ 13 ], and prostate [ 17 , 18 ]. The anti-cancer mechanisms of PGG are different from those of chemotherapeutic drugs.…”

Pentagalloyl Glucose-Targeted Inhibition of P-Glycoprotein and Re-Sensitization of Multidrug-Resistant Leukemic Cells (K562/ADR) to Doxorubicin: In Silico and Functional Studies

“…Studies have revealed that PGG exerts its anti-cancer effect through its anti-proliferative, pro-apoptotic, and anti-metastatic effects against various cancer cells, such as breast, lung, colon, and prostate cancers [ 18 , 19 , 20 , 21 ]. Moreover, PGG has been found to sensitize cancer cells to different anti-cancer agents and radiotherapy, rendering them more susceptible to treatment [ 22 , 23 , 24 ]. Notably, one intriguing mechanism by which PGG demonstrates its anti-cancer properties is by downregulating the expression of MDR1.…”