The selective cytotoxicity elicited by phytochemical extract from Senecio graveolens (Asteraceae) on breast cancer cells is enhanced by hypoxia

Abstract

Breast cancer is the second cause of cancer‑related deaths in woman and the incidence of the disease has increased worldwide, in part due to improvements in early detection. Several drugs with anticancer effects have been extracted from plants in the last 20 years, many of which are particularly effective against breast cancer cells. In particular, we have become interested in the ethanolic extract from Senecio graveolens (synonym of S. nutans), a plant commonly called Chachacoma, in an effort to isolate compounds that could demonstrate cytotoxic effects on breast cancer cells. Senecio (Asteraceae) is the largest gender in Chile comprising approximatly 200 species. These herbs inhabit areas over 3,500 meters above the sea level in the Andes Mountains. S. graveolens is commonly used by local communities for its medicinal properties, particularly its capacity to ameliorate high-altitude-associated sickness. The cytotoxic effect of the alcoholic extract from S. graveolens, as well as its most abundant compound 4-hydroxy-3-(3-methyl-2-butenyl)acetophenone, were tested in the breast cancer cell lines ZR-75-1, MCF-7 and MDA-MB‑231, and non-tumorigenic MCF-10F cells. We show that the phytochemical extract was able to induce cytotoxicity in cancer cells but not in MCF-10F. Importantly, this effect was enhanced under hypoxic conditions. However, 4-hydroxy-3-(3-methyl-2-butenyl)acetophenone, the main compound, did not by itself show an effective anticarcinogenic activity in comparison to the whole extract. Interestingly, the cytotoxic effect of the phytochemical extract was dependent on the basal MnSOD protein expression. Thus, cytotoxicity was increased when MnSOD levels were low, but resistance was evident when protein levels were high. Additionally, the crude extract seems to trigger cell death by a variety of processes, including autophagy, apoptosis and necrosis, in MCF-7 cells. In summary, S. graveolens extract possess anticancer activity displaying a specific cytotoxic effect on cancer cells, thus serving as a potential source of phytochemical compounds for cancer treatment.

Inhibition of HIF-1α through Suppression of NF-κB Activation by Compounds Isolated from Senecio graveolens

“…These results corroborate those shown by Echiburú-Chau et al [6], who by means of the neutral red uptake test observed that at a concentration of 200 μg/mL ethanolic extract of S. graveolens exhibited cytotoxicity in breast cancer cell lines ZR-75-1, MCF-7, and MDA-MB-231 at 24 h of treatment under hypoxic conditions, without damaging the MCF-10F cell line. However, at this concentration, the ethanolic extract of S. graveolens showed a greater cytotoxic effect on the cell line MDA-MB-231 (50 %) com-pared to the other cancer lines ZR-75-1 (9 %) and MCF-7 (6 %) [6]. Finally, both MTT and LDH assays showed that dichloromethane/ methanol and aqueous extracts have cytotoxic effects higher than 100 μg/mL in the PBMCs.…”

“…It should be noted that in the work of Echiburú-Chau et al [6] they mentioned that the majority compound [4-hydroxy-3-(3-methyl-2-butenyl) acetophenone] of the alcoholic extract presented less cytotoxic activity on different tumour cellular lines than the complete extract. However, in our case, the major compounds (phanurane, damsine, and scoparone) of the dichloromethane/ methanol extract showed greater cytotoxic activity over different tumour cellular lines than the complete extract (▶Table 3).…”

“…The decoction of leaves, stems, and roots is used against all types of pulmonary affections such as a brain tonic and against nervousness and excessive sweating [1,[3][4][5]. Pharmacological studies have shown that the ethanolic extract of S. graveolens possesses cytotoxic activity in MCF-7 cancer cells at a concentration of 200 μg/mL [6]. Human cancers frequently contain areas of necrosis in which cancer cells have died due to inadequate oxygenation [7,8].…”

Phytochemicals based chemopreventive and chemotherapeutic strategies and modern technologies to overcome limitations for better clinical applications

“…Some studies have demonstrated that certain phytochemicals have better selectivity than chemically derived drugs. For example, the ethanolic extract of Senecio graveolens causes selective cytotoxicity in breast cancer cells via hypoxia-mediated mitochondrial dysfunction and oxidative stress (Echiburu-Chau et al, 2014). Ashwagandha leaf extract and its purified component Withanone have been shown to cause selective killing of cancer cells by inducing reactive oxygen species (ROS)-mediated damage (Widodo, Priyandoko, Shah, Wadhwa, & Kaul, 2010).…”

Cytotoxic Activity of a Medicinal Mangrove Plant Ceriops Decandra (Griff.) Ding Hou Leaves on Human Breast Adenocarcinoma Cell Line McF-7

“…[4], Senecio graveolens Wedd. [5], and Salicornia brachiata Roxb. [6] practiced worldwide by various traditional healers, and natural products such as Hypnea musciformis [7] and jadomycins [8] biosynthesized by the soil bacteria Streptomyces venezuelae are yet to be screened for its potential therapeutic effects.…”