Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors originating from chromaffin cells in the adrenal medulla (PCCs) or extra-adrenal sympathetic or parasympathetic paraganglia (PGLs). About 40% of PPGLs result from germline mutations and therefore they are highly inheritable. Although dysfunction of any one of a panel of more than 20 genes can lead to PPGLs, mutations in genes involved in the VHL/HIF axis including PHD, VHL, HIF-2A (EPAS1), and SDHx are more frequently found in PPGLs. Multiple lines of evidence indicate that pseudohypoxia plays a crucial role in the tumorigenesis of PPGLs, and therefore PPGLs are also known as metabolic diseases. However, the interplay between VHL/HIF-mediated pseudohypoxia and metabolic disorder in PPGLs cells is not well-defined. In this review, we will first discuss the VHL/HIF axis and genetic alterations in this axis. Then, we will dissect the underlying mechanisms in VHL/HIF axis-driven PPGL pathogenesis, with special attention paid to the interplay between the VHL/HIF axis and cancer cell metabolism. Finally, we will summarize the currently available compounds/drugs targeting this axis which could be potentially used as PPGLs treatment, as well as their underlying pharmacological mechanisms. The overall goal of this review is to better understand the role of VHL/HIF axis in PPGLs development, to establish more accurate tools in PPGLs diagnosis, and to pave the road toward efficacious therapeutics against metastatic PPGLs.

Prostate cancer is one of the most common cancers diagnosed in men in the United States and the second leading cause of cancer-related deaths worldwide. Since over 60% of prostate cancer cases occur in men over 65 years of age, and this population will increase steadily in the coming years, prostate cancer will be a major cancer-related burden in the foreseeable future. Accumulating data from more recent research suggest that the tumor microenvironment (TME) plays a previously unrecognized role in every stage of cancer development, including initiation, proliferation, and metastasis. Prostate cancer is not only diagnosed in the late stages of life, but also progresses relatively slowly. This makes prostate cancer an ideal model system for exploring the potential of natural products as cancer prevention and/or treatment reagents because they usually act relatively slowly compared to most synthetic drugs. Resveratrol (RSV) is a naturally occurring stilbenoid and possesses strong anti-cancer properties with few adverse effects. Accumulating data from both in vitro and in vivo experiments indicate that RSV can interfere with prostate cancer initiation and progression by targeting the TME. Therefore, this review is aimed to summarize the recent advancement in RSV-inhibited prostate cancer initiation, proliferation, and metastasis as well as the underlying molecular mechanisms, with particular emphasis on the effect of RSV on TME. This will not only better our understanding of prostate cancer TMEs, but also pave the way for the development of RSV as a potential reagent for prostate cancer prevention and/or therapy.

Although melanoma affects both sexes, current literature shows it is more prevalent and more deadly in men. Several potential reasons for this difference have been proposed. That said, the androgen receptor has been proven to play a role in melanoma growth and metastasis, and may play a part in the difference in incidence and mortality rates between sexes. Resveratrol, a naturally occurring compound with poor bioavailability, has been shown to decrease melanoma cell growth in both in vitro and in vivo studies. Its effects on the expression of several genes involved in the androgen receptor pathway in non-melanoma cancer are well documented. Although several mechanisms have been proposed in which resveratrol affects melanoma cell growth, we suspect the androgen receptor pathway may be another target that warrants further investigation. Our objective is to reiterate the potential for resveratrol as a treatment in melanoma and to propose that it changes melanoma behavior at least partially through its interaction in the androgen receptor pathway. We also will discuss pros and cons of the various ways resveratrol may be delivered as a treatment for melanoma. To support our hypothesis we reviewed current literature and performed scratch wound assay, qPCR, and Western Blotting. Melanoma cells treated with resveratrol showed a decrease in the distance traveled during scratch wound assay. Additionally, androgen receptor pathway gene expression and protein level was altered in cells treated with resveratrol. The androgen receptor pathway plays a role in melanoma cell growth and metastasis. Resveratrol is a potential therapeutic that decreases melanoma growth at least partially through its effects on this pathway. Further melanoma in vivo studies that explore the various methods of treatment with resveratrol are needed to help the transition from bench to bedside.