Bioactive Natural Products against Prostate Cancer: Mechanism of Action and Autophagic/Apoptotic Molecular Pathways

Abstract

Introduction !Prostate cancer (PCa) is one of the most common malignancies in men and a leading cause of death worldwide for men. Taking into consideration that chemotherapy has severe side effects and usually a poor outcome, there is an intensive need for the development of safer and more effective agents. Since plants have been used by traditional medicine for the treatment of various diseases, in the last decades, many natural products have been isolated from plants and tested for their tumor selectivity and cytotoxic efficacy. Several of these naturally occurring compounds have been found to inhibit PCa growth and metastasis and are thus a promising approach for the treatment of this malignancy. Laboratory studies in different in vitro and in vivo systems have shown that these natural products modulate cellular processes, exhibit chemopreventive and/or chemotherapeutic effects, and induce apoptosis and autophagy. Accordingly, the antiproliferative and autophagic effects of nontoxic dietary agents could be of additional significance for the prevention, control, and management of PCa, specifically for the advanced and androgen-independent stage of the malignancy [1][2][3]. As there is increasing data on how natural compounds interfere with diverse molecular pathways in cancer cells, this review discusses the mechanism of action of bioactive natural products in the field of PCa and emphasizes the implicated molecular pathways of apoptosis and autophagy as important processes that control cellular homeostasis and that have been highlighted as promising targets for novel cancer therapies.Apigenin ! Apigenin (4′,5,7-trihydroxyflavone) is a flavone found in plants of the Asteraceae family, such as Anthemis sp., and many fruits and vegetables [4]. Apigenin has been tested in various types of cancer cell lines (breast, colon, liver, lung) showing promising results [5]. In prostate cancer in particular, apigenin administered in various concentrations (1-20 μΜ) for 24, 48, and 72 h not only causes G1 cell cycle arrest both in androgen-dependent (LNCaP) and -independent (DU145 and PC-3) PC cell lines through the decreased expression of cyclins D1, D2, and E, but also induces apoptosis through a shift in the Bax/Bcl-2 ratio [6,7]. Further studies in PC-3 cells have also demonstrated that apigenin (5-40 μΜ), delivered for 24 h, suppresses cell proliferation and induces apoptosis by inhibiting IGF-IGF-IR signaling and inactivating the PI3k/Akt pathway [8]. Apigenin Abstract ! Prostate cancer is one of the leading causes of death worldwide for men. There is increasing evidence that diet and lifestyle play a crucial role in prostate cancer biology and tumorigenesis. Due to the fact that conventional chemotherapy is not adequately effective against prostate cancer and has severe side effects, numerous in vitro studies have been conducted in order to identify the potent cytotoxic or chemopreventive activity of naturally occurring compounds and their respective molecular mechanisms of action. In this context, many natural compo...

Silymarin Enriched Extract (Silybum marianum) Additive Effect on Doxorubicin-Mediated Cytotoxicity in PC-3 Prostate Cancer Cells

“…Nevertheless, Davis-Searles et al showed that several compounds of the extract such as silybin B, isosilybin B, and taxifolin are effective in PC-3 cells [4]. Our findings coincide overall with previous studies that depict silymarinʼs and silibininʼs antiproliferative properties in a variety of cancer types in preclinical models [3]. Furthermore, the co-treatment with DXR-SEE and DXR-silibinin resulted in a substantial inhibition of cell proliferation even at very low doses of DXR (< 3 nM), suggesting a significant additive effect, as SEE and silibinin are able to lower the cytotoxic dose of DXR.…”

“…Hence, there is an urgent need to discover new supplementary treatments in order to reduce DXR cytotoxicity in normal cells without affecting and even enhancing its antitumor potential [2]. Over the last years, several natural dietary compounds have been tested for their cytotoxic or antitumor activity, showing promising results as they prevent the occurrence and/or spread of cancer either alone or in combination with chemotherapeutical agents [3]. SEE is a natural preparation obtained from the seeds of milk thistle (Silybum marianum [L.] Gaertn., Asteraceae), comprising of a number of flavonolignans and flavonoids, with silibinin (silybin A and silybin B) being the major bioactive component [4].…”

Ophiopogonin D′, a Natural Product From Radix Ophiopogonis, Induces in Vitro and in Vivo RIPK1-Dependent and Caspase-Independent Apoptotic Death in Androgen-Independent Human Prostate Cancer Cells

“…Natural compounds can induce the apoptosis of cancer cells by triggering caspase and mitochondria-dependent cascades, by inhibiting oncogenes, or by suppressing NFκB signaling ( Gioti and Tenta, 2015 ; Zhou et al, 2015 ). We herein demonstrated that OPD′ could induce apoptosis in PC3 cells via a caspase-independent pathway.…”

Bursera copallifera Extracts Have Cytotoxic and Migration-Inhibitory Effects in Breast Cancer Cell Lines

“… 16 - 26 Phytochemical studies of the genus Bursera have reported the presence of lignans, bilignans, flavonoids, flavonoid glycosides, steroids, short-chain aliphatic alkanes, acetates, alcohols, ketones, and terpenoids, the latter mostly monoterpenes while diterpenes and triterpenes occur at lesser extent. 5 , 6 , 18 , 27 - 33 Secondary metabolites belonging to these groups of compounds have been reported to have cytotoxic properties, 34 - 36 further suggesting a potential use of Bursera extracts in the treatment of cancer. Accordingly, extracts of B. ariensi, B. bicolor, B. linanoe, B. galeottiana, B. fagaroides, B. graveolens, B. microphylla , and B. schlechtendalli have been found to induce growth inhibitory effects in different cancer cell lines, and extracts from B. fagaroides, B. permollis, B. morelensis, B. microphylla, B. klugii , and B. schlechtendalii have also been shown to exert antitumor activity in mice.…”