Apoptotic and Nonapoptotic Activities of Pterostilbene against Cancer

Abstract

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.

Keywords: apoptosis; cancer metastasis; fibronectin; pterostilbene.

Figure 1

Genes and pathways involved in the tumor progression toward cancer metastasis. Metastasis is the final stage of a chronic tumor progression, starting from tumor transformation followed by early progression within the primary tumor tissues, blood-borne to become circulating tumor cells (CTCs), colonization into distant organs in which pre-metastatic niche has been built, and outgrowth as secondary tumor tissues. Listed are signaling pathways associated with intrinsic and extrinsic stimulations for apoptosis and with apoptosis-independent activities. Note: The genes marked in green are considered tumor suppressive and in red oncogenic. The arrows with broken lines indicate the directions and locations toward which particular cells are moving. The corresponding full names abbreviated are listed as follows: TMEs, tumor microenvironments; ECM, extracellular matrix; micro, micrometastasis; macro, macrometastasis; FN, fibronectin; BMDC, bone marrow derived cells; TNF, tumor necrosis factor family, ptw, pathway; mig, migration; inv, invasion.

Figure 2

The overview of anticancer properties of pterostilbene (trans-3,5-dimethoxy-4-hydroxystilbene; PS). PS are able to target apoptosis-dependent and -independent signaling pathways against cancer progression and likely cancer metastasis. The key events affected by PS in all the pathways are boxed in grey color. In the category of pro-apoptotic effects, PS inhibits onco-miRs (e.g., miR663b) and growth factors (e.g., EGFR), triggers an epigenetic modification through the inhibition of MTA1, induces ERS, or lowers autophagy through the inhibition of ATG1. In the category of nonapoptotic effects, most of the effects caused by PS are shown to inhibit pro-tumor signaling pathways including hTERT, Fas/FAK signaling, TNFα, cell growth/MMP-9, NF-κB/MUC1/β-catenin, AKT/ERK signaling axis, and packed in circulating sEVs that are involved in senescence prevention, EMT, inflammation, p38/mediated migration/invasion, and cancer stemness, polyFN assembly on CTCs, and miR17-92-delivery in the circulation, respectively. All these apoptosis-dependent and -independent inhibitory effects caused by PS likely lead to a reduction of cancer metastasis. Note: signaling events involved in the anti-metastatic activities of PS are depicted as solid or broken lines whenever supported or not yet supported (only logically deduced), respectively, by the literature. The corresponding full names abbreviated are listed as follows: ptw, pathway; meta, metastasis; gro, growth; mig, migration; inv, invasion.