Abstract
Cervical cancer is the fourth most common cancer that affects women, mainly through human papilloma virus (HPV) infection with high-risk HPV16 and HPV18. The present study investigated the in vitro anticancer activity and mechanism of action of a proanthocyanidin polymer-rich fraction of Stryphnodendron adstringens (F2) in cervical cancer cell lines, including HeLa (HPV18-positive), SiHa (HPV16-positive), and C33A (HPV-negative) cells, and also evaluated in vivo anticancer activity. In vitro, cell viability was determined by the MTT assay. Cell migration was determined by the wound healing assay. The mechanism of action was investigated by performing ultrastructural analysis and evaluating reactive oxygen species (ROS) production, mitochondrial metabolism, lipoperoxidation, BCL-2 family expression, caspase expression, and DNA and cell membrane integrity. In vivo activity was evaluated using the murine Ehrlich solid tumor model. F2 time- and dose-dependently reduced cell viability and significantly inhibited the migration of cervical cancer cells. HeLa and SiHa cells treated with F2 (IC50) exhibited intense oxidative stress (i.e., increase in ROS and decrease in antioxidant species) and mitochondrial damage (i.e., mitochondrial membrane potential depolarization and a reduction of intracellular levels of adenosine triphosphate). Increases in the Bax/BCL-2 ratio and caspase 9 and caspase 3 expression, were observed, with DNA damage that was sufficient to trigger mitochondria-dependent apoptosis. Cell membrane disruption was observed in C33A cells (IC50 and IC90) and HeLa and SiHa cells (IC90), indicating progress to late apoptosis/necrosis. The inhibition of ROS production by N-acetylcysteine significantly suppressed oxidative stress in all three cell lines. In vivo, F2 significantly reduced tumor volume and weight of the Ehrlich solid tumor, and significantly increased lipoperoxidation, indicating that F2 also induces oxidative stress in the in vivo model. These findings indicate that the proanthocyanidin polymer-rich fraction of S. adstringens may be a potential chemotherapeutic candidate for cancer treatment.
Highlights
MATERIALS AND METHODSCervical cancer is the fourth most common cancer that affects women worldwide (Graham, 2017)
The aim of the present study was to investigate the prooxidant properties of a proanthocyanidin polymer-rich fraction of S. adstringens (F2) through the in vitro anticancer activity and mechanism of action in cervical cancer cell lines, including HeLa, SiHa, and C33A cells, and to evaluate in vivo anticancer activity in a murine Ehrlich solid tumor model
HeLa, SiHa, and C33A cells were plated at a density of 2.5 × 105 cells/ml for 24 h at 37◦C under a 5% CO2 atmosphere
Summary
MATERIALS AND METHODSCervical cancer is the fourth most common cancer that affects women worldwide (Graham, 2017). The genotoxic and acute and chronic toxicity of this plant have been assessed in rodents (Costa et al, 2010, 2013). This plant has been shown to be cytotoxic for human breast cancer cells (Sabino et al, 2017). The proanthocyanidin polymer-rich fraction of S. adstringens stem bark is rich in condensed tannins, or proanthocyanidins, including several flavan-3-ols, such as prodelphinidins and prorobinetinidins (de Mello et al, 1996a,b, 1999; Ishida et al, 2006)
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