Molecular mechanisms of cholangiocarcinoma cell inhibition by medicinal plants

Abstract

Abstract. Cholangiocarcinoma (CCA) is one of the most common causes of cancer-associated mortality in Thailand. Certain phytochemicals have been demonstrated to modulate apoptotic signaling pathways, which may be targeted for the prevention and treatment of cancer. Therefore, the aim of the present study was to investigate the effect of specific medicinal plants on the inhibition of CCA cell proliferation, and to identify the molecular mechanisms underlying this. A WST-1 cell proliferation assay was performed using an RMCCA1 cell line, and apoptotic signaling pathways were also investigated using a PathScan Stress and Apoptosis Signaling Antibody Array Kit. The cell proliferation assay indicated that extracts from the Phyllanthus emblica fruit pulp (PEf), Phyllanthus emblica seed (PEs), Terminalia chebula fruit pulp (TCf), Terminalia chebula seed (TCs), Areca catechu seed (ACs), Curcuma longa (CL) and Moringa oleifera seed (MOs) exerted anti-proliferative activity in RMCCA1 cells. In addition, the PathScan assay revealed that certain pro-apoptotic molecules, including caspase-3, poly (ADP-ribose) polymerase, checkpoint kinase 2 and tumor protein 53, exhibited increased activity in RMCCA1 cells treated with the aforementioned selected plant extracts, with the exception of PEf. The mitogen-activated protein kinase (MAPK) pathways (including ERK1/2 and p38 MAPK) expression level was significantly increased in RMCCA1 cells pre-treated with extracts of PEs, TCf, CL and MOs. The activation of protein kinase B (Akt) was significantly demonstrated in RMCCA1 cells pre-treated with extracts of TCf, ACs and MOs. In summary, the present study demonstrated that extracts of PEs, TCf, TCs, ACs, CL and MOs exhibited anti-proliferative effects in CCA cells by inducing pro-apoptotic signals and modulating signal transduction molecules. Further studies in vivo are required to demonstrate the potential applications of specific plant extracts for the treatment of human cancer.

Nontoxic Glucomoringin-Isothiocyanate (GMG-ITC) Rich Soluble Extract Induces Apoptosis and Inhibits Proliferation of Human Prostate Adenocarcinoma Cells (PC-3)

“…Furthermore, the extract was reported to have triggered apoptosis through the activation of phosphor-extracellular signal related kinase (p-ERK) and phosphor-c-Jun N-terminal kinase (pJNK) in human melanoma cancer cells (A2058) [ 69 ]. Similarly, an extract from M. oleifera seeds caused an increase in the phosphorylation level of ERK1/2 and p38 MAPK, which led to apoptosis in RMCCA1 [ 70 ]. The authors suggested that the activities of pro- and anti-apoptotic markers could be the benchmark for the apoptotic nature of the extract.…”

Nutraceutical or Pharmacological Potential of Moringa oleifera Lam.

“…In addition, the administration of M. oleifera leaf extract resulted in a time-dependent increase of phosphor-c-Jun N-terminal kinase (p-JNK) and phosphor-extracellular signal-related kinase (p-ERK), without changes in total JNK or ERK protein, hinting at the possibility of a pro-apoptotic role of M. oleifera via activation of these kinases in human melanoma A2058 cells [ 61 ]. Interestingly, in cholangiocarcinoma (CCA), the phosphorylation levels of phospho-p44/42 MAPK (ERK1/2) and phospho-p38 MAPK increased in M. oleifera seed extract treated RMCCA1 cells, suggesting that the activity levels of anti- and pro-apoptotic signaling proteins may determine the apoptotic nature of this compound [ 62 ]. The extracts from M. oleifera leaves and bark also effectively arrest cell cycle progression at the G2/M phase and increase apoptosis in breast and colorectal cancer cell lines such as MDA-MB-231 and HCT-8 cells, which could be attributed to the bioactive compounds such as eugenol, isopropyl isothiocynate, D-allose, and hexadeconoic acid ethyl ester [ 52 ].…”

Plantas Medicinais e seus Compostos com Potencial Terapêutico no Tratamento do Câncer: Revisão Integrativa

“…Nesta revisão, foi possível avaliar que os compostos curcumina, epicatequina, lupeol, ácido cafeico, ácido ursólico e berberina se destacaram em virtude da sua atividade contra diversos tipos de câncer, especialmente em estudos in vitro, em que esses compostos foram isolados de plantas medicinais aplicadas em ensaios. A curcumina pode ser encontrada principalmente na Curcuma longa, e demostrou efeito sobre a diminuição da viabilidade celular do câncer de mama e de cólon, por promover acúmulo de espécies reativas de oxigênio (ERO), que pode promover estresse celular, fazendo com que a célula entre em processo de apoptose 32,81 .…”