Abstract
Natural polyphenols are organic chemicals which contain phenol units in their structures and possess antitumor properties. However, a key problem is their short half-life and low bioavailability under in vivo conditions. Pterostilbene (3,5-dimethoxy-4′-hydroxystilbene; PT) is a phytoalexin originally isolated from the heartwood of red sandalwood. As recently reported by our group, PT was shown to be effective in the treatment of melanoma. Counterintuitively, PT is not effective (cytotoxic) against melanoma in vitro, and only under in vivo conditions does PT display its anticancer activity. This study elucidated that PT can be effective against melanoma through the inhibition of adrenocorticotropic hormone production in the brain of a mouse, which weakens the Nrf2-dependent antioxidant defenses of melanoma and also pancreatic cancers. This results in both the inhibition of tumor growth and sensitization of the tumor to oxidative stress. Moreover, PT can promote cancer cell death via a mechanism involving lysosomal membrane permeabilization. Different grades of susceptibility were observed among the different cancer cells depending on their lysosomal heat shock protein 70 content, a known stabilizer of lysosomal membranes. In addition, the safety of PT administered i.v. has been evaluated in mice. PT was found to be pharmacologically safe because it showed no organ-specific or systemic toxicity (including tissue histopathologic examination and regular hematology and clinical chemistry data) even when administered i.v. at a high dose (30 mg/kg per day × 23 days). Moreover, new pharmacological advances are being developed to increase its bioavailability and, thereby, its bioefficacy. Therefore, although applications of PT in cancer therapy are just beginning to be explored, it represents a potential (and effective) adjuvant/sensitizing therapy which may improve the results of various oncotherapies. The aim of this review is to present and discuss the results that in our opinion best support the usefulness of PT in cancer therapy, making special emphasis on the in vivo evidence.
Highlights
At present, combined therapies involving distinct molecular mechanisms are considered the most promising strategies for cancer treatment
This study presented evidence that PT is working through reduction of NF-κB activation, decreasing the expression of inducible nitric oxide synthase, cyclooxygenase 2 (COX-2) and aldose reductase as well as through activation of Nrf-2 [48]
PT stands out in its ability to cross the blood–brain barrier, which may confer the potential advantage of being useful in the therapy of tumors of the central nervous system, such as glioblastoma multiforme
Summary
At present, combined therapies involving distinct molecular mechanisms are considered the most promising strategies for cancer treatment. A rise in intracellular reactive oxygen species (ROS) levels has two potentially important effects: damage to various cell components and triggering of the activation of specific signalling pathways. Both effects can influence numerous cellular processes linked to cancer progression. The net result of pro- and anti-cancer ROS effects may likely determine the rate and extent of in vivo tumor progression Based on this reasoning, elevated rates of intrinsic reactive oxygen species (ROS) generation may confer a higher susceptibility of cancer cells to further oxidative stress induced by treatments. In many cancer cells the Keap1-mediated Nrf downregulation is abolished or diminished, generating an addiction to Nrf and, thereby, favoring cancer cell defenses and progression [15]
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