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Fulltext Hydroxychavicol, a polyphenol from Piper betle leaf extract, induces cell cycle arrest and apoptosis in TP53-resistant HT-29 colon cancer cells

Rajedadram A, Pin KY, Ling SK, Yan SW, Looi ML

J Zhejiang Univ Sci B, 2021 Feb 15;22(2):112-122.
PMID: 33615752 DOI: 10.1631/jzus.B2000446

This study aims to elucidate the antiproliferative mechanism of hydroxychavicol (HC). Its effects on cell cycle, apoptosis, and the expression of c-Jun N-terminal kinase (JNK) and P38 mitogen-activated protein kinase (MAPK) in HT-29 colon cancer cells were investigated. HC was isolated from Piper betle leaf (PBL) and verified by high-performance liquid chromatography (HPLC), nuclear magnetic resonance (NMR), and gas chromatography-mass spectrometry (GC-MS). The cytotoxic effects of the standard drug 5-fluorouracil (5-FU), PBL water extract, and HC on HT-29 cells were measured after 24, 48, and 72 h of treatment. Cell cycle and apoptosis modulation by 5-FU and HC treatments were investigated up to 30 h. Changes in phosphorylated JNK (pJNK) and P38 (pP38) MAPK expression were observed up to 18 h. The half maximal inhibitory concentration (IC50) values of HC (30 μg/mL) and PBL water extract (380 μg/mL) were achieved at 24 h, whereas the IC50 of 5-FU (50 μmol/L) was obtained at 72 h. Cell cycle arrest at the G0/G1 phase in HC-treated cells was observed from 12 h onwards. Higher apoptotic cell death in HC-treated cells compared to 5-FU-treated cells (P<0.05) was observed. High expression of pJNK and pP38 MAPK was observed at 12 h in HC-treated cells, but not in 5-FU-treated HT-29 cells (P<0.05). It is concluded that HC induces cell cycle arrest and apoptosis of HT-29 cells, with these actions possibly mediated by JNK and P38 MAPK.
Fulltext Anti-migratory effects of Piper betle leaf aqueous extract on cancer cells and its microtubule targeting properties

Looi ML, Wong AKH, Gnapragasan SA, Japri AZ, Rajedadram A, Pin KY

J Zhejiang Univ Sci B, 2020 9 8;21(9):745-748.
PMID: 32893531 DOI: 10.1631/jzus.B2000278

Piper betle (PB), also known as "betel" in Malay language, is a tropical Asian vine. PB leaves are commonly chewed by Asians along with betel quid. It contains phenols such as eugenol and hydroxychavicol along with chlorophyll, β-carotene, and vitamin C (Salehi et al., 2019). Extracts from PB leaves have various medicinal properties including anticancer, antioxidant, anti-inflammatory, and antibacterial effects (Salehi et al., 2019). Previous research has shown that PB induces cell cycle arrest at late S or G2/M phase and causes apoptosis at higher doses (Wu et al., 2014; Guha Majumdar and Subramanian, 2019). A combination of PB leaf extract has also been shown to enhance the cytotoxicity of the anticancer drug, 5-fluorouracil (5-FU), in cancer cells (Ng et al., 2014).
Effects of drying on total polyphenols content and antioxidant properties of Carica papaya leaves

Yap JY, Hii CL, Ong SP, Lim KH, Abas F, Pin KY

J Sci Food Agric, 2020 May;100(7):2932-2937.
PMID: 32031257 DOI: 10.1002/jsfa.10320

BACKGROUND: Papaya is widely grown in Malaysia and normally only the fruits are consumed. Other parts of the plant such as leaves, roots, bark, peel, seeds and pulp are also known to have medicinal properties and have been used to treat various diseases. Papaya leaves also contain flavonoids, alkaloids phenolic compounds and cynogenetic compounds, and are also reported to be able to treat dengue fever.
RESULTS: Studies were carried out on drying of papaya leaves using hot air (60, 70 and 80 °C), shade and freeze drying. Effective diffusivities were estimated ranging from 2.09 × 10-12 to 2.18 × 10-12 m2 s-1 from hot air drying, which are within the order of magnitudes reported for most agricultural and food products. The activation energy to initiate drying showed a relatively low value (2.11 kJ mol-1 ) as a result of the thin leave layer that eased moisture diffusion. In terms of total polyphenols content and antioxidant activities, freeze-dried sample showed a significantly higher (P
Fulltext Piper betle leaf extract enhances the cytotoxicity effect of 5-fluorouracil in inhibiting the growth of HT29 and HCT116 colon cancer cells

Ng PL, Rajab NF, Then SM, Mohd Yusof YA, Wan Ngah WZ, Pin KY, et al.

J Zhejiang Univ Sci B, 2014 Aug;15(8):692-700.
PMID: 25091987 DOI: 10.1631/jzus.B1300303

OBJECTIVE: The combination effect of Piper betle (PB) and 5-fluorouracil (5-FU) in enhancing the cytotoxic potential of 5-FU in inhibiting the growth of colon cancer cells was investigated.
METHODS: HT29 and HCT116 cells were subjected to 5-FU or PB treatment. 5-FU and PB were then combined and their effects on both cell lines were observed after 24 h of treatment. PB-5-FU interaction was elucidated by isobologram analysis. Apoptosis features of the treated cells were revealed by annexin V/PI stain. High-performance liquid chromatography (HPLC) was performed to exclude any possible chemical interaction between the compounds.
RESULTS: In the presence of PB extract, the cytotoxicity of 5-FU was observed at a lower dose (IC50 12.5 µmol/L) and a shorter time (24 h) in both cell lines. Both cell lines treated with 5-FU or PB alone induced a greater apoptosis effect compared with the combination treatment. Isobologram analysis indicated that PB and 5-FU interacted synergistically and antagonistically in inhibiting the growth of HT29 and HCT116 cells, respectively.
CONCLUSIONS: In the presence of PB, a lower dosage of 5-FU is required to achieve the maximum drug effect in inhibiting the growth of HT29 cells. However, PB did not significantly reduce 5-FU dosage in HCT116 cells. Our result showed that this interaction may not solely contribute to the apoptosis pathway.
KEYWORDS: 5-Fluorouracil; Herb-drug interaction; Isobologram analysis; Piper betle L.; Piperaceae