Cancer is a major cause of death. The outcomes of current therapeutic strategies against cancer often ironically lead to even increased mortality due to the subsequent drug resistance and to metastatic recurrence. Alternative medicines are thus urgently needed. Cumulative evidence has pointed out that pterostilbene (trans-3,5-dimethoxy-4-hydroxystilbene, PS) has excellent pharmacological benefits for the prevention and treatment for various types of cancer in their different stages of progression by evoking apoptotic or nonapoptotic anti-cancer activities. In this review article, we first update current knowledge regarding tumor progression toward accomplishment of metastasis. Subsequently, we review current literature regarding the anti-cancer activities of PS. Finally, we provide future perspectives to clinically utilize PS as novel cancer therapeutic remedies. We, therefore, conclude and propose that PS is one ideal alternative medicine to be administered in the diet as a nutritional supplement.

Major cancer deaths can be ascribed to distant metastasis to which the assembly of pericellular fibronectin (periFN) on suspended tumor cells (STCs) in the bloodstream that facilitate endothelial attachment can lead. Even though mangosteen pericarps (MP) extracts and the major component α-mangostin (α-MG) exhibit potent cancer chemopreventive properties, whether they can prophylactically and therapeutically be used as dietary nutraceuticals to prevent distant metastasis by suppressing periFN assembly on STCs within the circulation remains obscure. Immunofluorescence staining, MTT assays, flow cytometric assays, immunoblotting, and experimental metastasis mouse models were used to detect the effects of MP extracts or α-MG on periFN on STCs, tumor cell proliferation and apoptosis, the AKT activity, and tumor lung metastasis. The periFN assembly on STCs was significantly diminished upon treatments of STCs with either α-MG or MP extracts in a dose-dependent manner without inhibiting cell proliferation and viability due to increased AKT activity. Pretreatment of STCs with α-MG appeared to suppress tumor lung metastasis and prolong mouse survival rates. Oral gavage with MP extracts could therapeutically, but not prophylactically, prevent lung metastasis of STCs. We concluded that MP extracts or the major component α-MG may therapeutically serve as a potent anti-metastatic nutraceutical.

Cytotoxic cancer therapies often result in unwanted side effects, drug resistance, and cancer metastasis. To avoid this, an anti-metastatic therapeutic strategy independent of apoptosis is alternatively desired. Malignant circulating tumor cells (CTCs) may escape from anoikis by sustaining AKT survival signals. Moreover, cancerous fibronectin polymers (polyFN) are known to mediate the adhesion of CTCs to endothelia and lung metastasis. Depletion of polyFN from CTCs without lowering AKT signaling may thus be an ideal anti-metastatic approach. Screening several phytochemical compounds, we found that Pterostilbene (PS), a resveratrol derivative, potently reduced polyFN on suspended tumor cells, whereas it significantly elevated AKT phosphorylation (pAKT), apparently in contrast to its well-known anti-apoptotic effect on adherent tumor cells. Inactivation of ERK signaling in suspended tumor cells was responsible for the enhanced pAKT by PS, leading to suppressions of polyFN assembly and tumor metastasis. Pretreatment with a PI3K inhibitor, LY294002, effectively reduced PS-activated AKT, rescued PS-inactivated ERK, and consequently reversed the PS-suppressed polyFN assembly which was then overturned by the ERK inhibitor U0126. Indeed, PS-suppressed lung metastasis was counteracted by LY294002, which was reversed with U0126. Dietary PS may serve as a novel complementary medicine, for it could be orally administered and efficiently blockaded tumor metastasis by targeting AKT-ERK signaling axis in CTCs. Citation Format: Hung-Chi Cheng, Ying-Jan Wang, Li-Hsin Cheng. AKT-ERK axis in circulating tumor cells is a target for metastatic suppression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4178.