Ethanolic extract of Thevetia peruviana flowers enhances TNF-α and TRAIL-induced apoptosis of human cervical cancer cells via intrinsic and extrinsic pathways

Abstract

Abstract. Tumor necrosis factor-α (TNF-α) and TNF-related apoptosis-inducing ligand (TRAIL) are promising candidates for cancer treatment due to their ability to induce apoptosis through death receptor stimulation. However, their usage may be limited due to the resistance of cancer cells to TNF-α-and TRAIL-induced apoptosis. Currently, there is interest in screening for natural products that can sensitize cancer cells to TNF-α-and TRAIL-induced apoptosis for their use in combination with TNF-α or TRAIL. It was previously reported that the bark extract of Thevetia peruviana showed a reversal effect on TRAIL-resistance in human gastric adenocarcinoma cell lines. In the present study, the effects of the ethanolic extract of T. peruviana flowers on TNF-α-and TRAIL-induced apoptosis of human cervical cancer HeLa cells were investigated in vitro by determining cell viability and apoptosis using a WST-1 cell proliferation assay and immunoblot analysis, respectively. The ethanolic extract of T. peruviana flowers promoted TNF-α and TRAIL-mediated cell death through the activation of the caspase cascade, poly(ADP-ribose) polymerase and BH3-interacting domain death agonist cleavage. Combined treatment using the extract plus TNF-α resulted in downregulation of anti-apoptotic protein, including myeloid cell leukemia sequence-1, B-cell lymphoma-extra large (Bcl-XL), X-linked inhibitor of apoptosis protein and survivin, while the combined treatment with TRAIL downregulated Bcl-XL. Thus, the ethanolic extract of T. peruviana flowers has potential in sensitizing the TNF-α-and TRAIL-induced apoptosis of HeLa cells via the intrinsic and extrinsic pathways. IntroductionChemotherapy is one of the major standard treatments that is beneficial for numerous cancer types due to its efficient induction of tumor cell death by apoptosis. At present, the cancer resistance of chemotherapeutic drugs is a major drawback that leads to the failure of cancer treatments. Chemotherapeutic drugs eliminate tumor cells by the induction of apoptosis via two distinct pathways, which act through the mitochondria (intrinsic signaling pathway) or through death receptors on the cell surface (extrinsic signaling pathway) (1). Induction of apoptosis via the intrinsic signaling pathway is initiated by severe cell stress, including DNA damage, mitotic catastrophe, hypoxia and cell cycle checkpoint defects. The majority of conventional chemotherapeutic drugs trigger DNA damage and induce apoptosis via the intrinsic signaling pathway by the activation of tumor suppressor protein, p53, which leads to the breakdown of mitochondrial membrane and the release of cytochrome c into the cytosol. Cytochrome c binds to the adaptor apoptotic protease activating factor 1, forming an apoptosome. The apoptosome subsequently activates caspase-9 and caspase-3, which results in the cleavage of death substrates (2-4). Defects in intrinsic apoptosis signal transduction, such as the mutation of p53, contributes to the chemotherapeutic drug resistance of cancer (5,6). The extrinsic pa...

A Comprehensive Understanding of the Anticancer Mechanisms of FDY2004 Against Cervical Cancer Based on Network Pharmacology

“…[79][80][81][82][83][84][85][86] The expression and activity of TNF-α (encoded by TNF) is associated with the apoptosis, chemosensitivity, DNA damage response, necrosis, proliferation, invasion, and EMT of CC cells, and its polymorphisms are further correlated with the risk of development, progression, and malignancy in patients with CC. [87][88][89][90][91][92][93][94][95][96][97][98][99][100] The genetic or epigenetic malfunction of p53 (encoded by TP53), a key tumor suppressor that coordinates the cell cycle process, proliferation, apoptosis, DNA damage repair, and metabolism, can drive CC pathogenesis; therefore, the restoration of its expression or functional activity has been suggested as a potential strategy for treating CC. [101][102][103] In addition, elevated expression and polymorphisms of TP53 are commonly observed in CC tissues compared to normal cervical tissues, and correlated with the poor clinical outcome of patients with CC.…”

Anticancer Efficacy of Thevetia peruviana (Pers.) K. Schum. Extracts on Triple Negative Human Breast Cancer Cell Line

“…possess potential anticancer activities. Managit C et al [13] reported that the ethanolic extract of flowers were effective against the HeLa cells. Silva AR et al [14] Testified that the methanolic extract of the fruits possess anticancer potential against the human breast, colorectal, prostate and lung cancer cell lines.…”

Flowers for cancer treatment: From beauty to duty

“…Thus, the ethanolic FE of Thevetia peruviana stimulated apoptosis of cervical cancer HeLa cells triggered by TNFα or TRAIL, two ligands of death receptors, by activating caspase-3 and PARP. Notably, FE of T. peruviana diminished the expression of the anti-apoptotic protein survivin (Managit, Sakurai, and Saiki, 2017) A FE containing essential oils of Pallines spinosa decreased cell viability of breast cancer cells while a minor effect was detected in immortalized mammary epithelial cells (Saleh et al, 2017). This effect was accompanied by a decrease of the anti-apoptotic protein Bcl-2 and an increase of the pro-apoptotic protein Bax Flowers from Antirrhium majus are among the most popular edible flowers, frequently used from preparing foods and drinks.…”