Abstract
Despite the advances in cancer therapy and early detection, breast cancer remains a leading cause of cancer-related deaths among females worldwide. The aim of the current study was to investigate the antitumor activity of a novel compound, 4-(3,4,5-trimethoxyphenoxy)benzoic acid (TMPBA) and its mechanism of action, in breast cancer. Results indicated the relatively high sensitivity of human breast cancer cell-7 and MDA-468 cells towards TMPBA with IC50 values of 5.9 and 7.9 μM, respectively compared to hepatocarcinoma cell line Huh-7, hepatocarcinoma cell line HepG2, and cervical cancer cell line Hela cells. Mechanistically, TMPBA induced apoptotic cell death in MCF-7 cells as indicated by 4′,6-diamidino-2-phenylindole (DAPI) nuclear staining, cell cycle analysis and the activation of caspase-3. Western blot analysis revealed the ability of TMPBA to target pathways mediated by mitogen-activated protein (MAP) kinases, 5′ adenosine monophosphate-activated protein kinase (AMPK), and p53, of which the concerted action underlined its antitumor efficacy. In addition, TMPBA induced alteration of cyclin proteins’ expression and consequently modulated the cell cycle. Taken together, the current study underscores evidence that TMPBA induces apoptosis in breast cancer cells via the modulation of cyclins and p53 expression as well as the modulation of AMPK and mitogen-activated protein kinases (MAPK) signaling. These findings support TMPBA’s clinical promise as a potential candidate for breast cancer therapy.
Highlights
Breast cancer is one of the most common and deleterious of all diseases affecting females in addition to being the second leading cause of death among women worldwide [1,2]
To investigate the anti-proliferative effects of TMPBA (Figure 1), five human cancer cell lines were examined in response to TMPBA treatment: Huh-7, HepG2, Hela, MCF-7, and MDA-468
The breast cancer cell lines MCF-7 and MDA-468 were very sensitive to TMPBA
Summary
Breast cancer is one of the most common and deleterious of all diseases affecting females in addition to being the second leading cause of death among women worldwide [1,2]. While many breast cancer patients initially respond to chemotherapy, resistance often rapidly develops which leads to poor clinical prognosis [8]. Apoptosis is a highly regulated process of programmed cell death, and disruption of this process represents a major contributing factor in the pathology of cancer [9]. The activation of caspases induces protein cleavage which results in chromatin condensation, DNA fragmentation, and cell shrinkage [14]. Another major player in apoptosis process is p53 which is activated when mammalian cells are subjected to stress conditions such as hypoxia, radiation, DNA damage or chemotherapeutic drugs [15,16]. In addition to its role in suppressing tumorigenesis, p53 contributes to chemotherapy-induced cell death [17]. In addition to its role in suppressing tumorigenesis, p53 contributes to chemotherapy-induced cell death [17]. p53 mediates apoptosis through a linear pathway involving Bax transactivation, mitochondrial cytochrome c release mitochondria and caspase-9 activation, followed by the activation of caspase-3, -6, and -7 [18,19]
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