Synthetic Resveratrol Analogue, 3,3',4,4',5,5'-Hexahydroxy-trans-Stilbene, Accelerates Senescence in Peritoneal Mesothelium and Promotes Senescence-Dependent Growth of Gastrointestinal Cancers

Abstract

3,3′,4,4′,5,5′-Hexahydroxy-trans-stilbene (M8) is a synthetic resveratrol derivative, advertised as a candidate drug highly effective against numerous malignancies. Because multiple tumors prone to M8 frequently metastasize into the peritoneal cavity, this study was aimed at establishing the effect of M8 on the growth and senescence of human peritoneal mesothelial cells (HPMCs), the largest cell population within the peritoneum, actively involved in the intraperitoneal spread of cancer. The study showed that M8, used at the highest non-toxic dose of 10 μM, impairs proliferation and accelerates senescence in cultured HPMCs via an oxidative stress-dependent mechanism. At the same time, soluble factors released to the environment by HPMCs that senesced prematurely in response to M8 promoted growth of colorectal and pancreatic carcinomas in vitro. These findings indicate that M8 may indirectly—through the modification of normal (mesothelial) cells phenotype—facilitate an expansion of cancer cells, which challenges the postulated value of this stilbene in chemotherapy.

A resveratrol analog termed 3,3′,4,4′,5,5′-hexahydroxy-trans-stilbene is a potent HIV-1 inhibitor

“…In fact, several synthetic resveratrol derivatives exhibit anti‐HIV‐1 activity that is superior to that of resveratrol [Piao et al, ; Clouser et al, ]. It had been believed that the introduction of additional groups into the stilbene ring of resveratrol would strengthen the biological properties of resveratrol analogs [Horvath et al, ; Mikula‐Pietrasik et al, ]. In fact, increasing the number of hydroxy‐moieties in the stilbene ring of resveratrol does result in higher anti‐HIV‐1 activity than is associated with resveratrol itself [Piao et al, ; Clouser et al, ], and this is confirmed here for M8.…”

“…It is believed that an increase in the number of hydroxyl groups on resveratrol could enhance its biological effects [Horvath et al, ]. Among several synthetic resveratrol derivatives containing an increasing number of hydroxy‐ and/or methoxy‐groups, 3,3′,4,4′,5,5′‐hexahydroxy‐stilbene (M8) was shown to be a promising agent [Murias et al, ; Horvath et al, ; Mikula‐Pietrasik et al, ].…”

Therapeutic Versatility of Resveratrol Derivatives

“…3,3′,4,4′,5,5′-hexahydroxy- trans -stilbene (3,3′,4,4′,5,5′-HDS) is a synthetic resveratrol derivative, advertised as a candidate drug highly effective against various pathophysiological process. The presence of additional hydroxy (–OH) groups in the highly reactive position ortho can enhance its biological activities [ 130 ]. Another property exacerbated by the additional ortho-hydroxyl groups was the generation of mitochondrial reactive oxygen species (ROS), especially superoxides, whose deleterious activity might underlie either anti-proliferative or pro-apoptotic capabilities of 3,3′,4,4′,5,5′-HDS [ 22 ].…”

“…The presence of ortho-hydroxyl groups in 3,3′,4,4′,5,5′-HDS structure increased its cytotoxicity and biological activities. 3,3′,4,4′,5,5′-HDS metastasized numerous cancers into peritoneal cavity [ 130 ]. In human breast cancer cells, 3,3′,4,4′,5,5′-HDS induced cytotoxicity by apoptosis, of cell proliferation and clonogenic survival [ 131 , 132 ].…”

Identification of resveratrol analogs as potent anti‐dengue agents using a cell‐based assay

“…We have previously shown that a resveratrol derivative, originally designed as an anti-cancer agent [Mikula-Pietrasik et al, 2013], possesses anti-HIV activity as well [Han et al, 2015]. Therefore, in the current study, we have investigated some new resveratrol derivatives, designed for anti-cancer activity, to determine whether they might serve as a source of hits-to-leads in the development of novel anti-DENV drugs.…”