In 2008 it is estimated that over 200,000 new cases of prostate cancer will be diagnosed and over 27,000 prostate related cancer deaths will occur. Multiple signaling pathways that include nuclear factor kappa B, Phosphotidyl Inositol 3 Kinase/Akt signaling network as well as others are behaving in a manner that promotes the persistence and proliferation of prostate cancer. Since the majority of chemotherapeutic agents have been designed in such a fashion to target one specific protein or pathway and they will often fail to inhibit the growth of prostate cancer in preclinical and clinical settings. Therefore, it is essential that novel small molecules (e.g. dietary agents) be identified that have an innate ability to target multiple signaling pathways. Over the last several years it is becoming increasingly appreciated that dietary agents have an innate ability to target multiple deregulated pathways in cancer and more importantly may be an effective strategy that can be translated to the clinic. It is on this principle that we have identified a novel dietary agent, alpha-Mangostin, a non- nutrient and non-toxic natural agent present in the Mangosteen fruit (Garcinia mangostana). Alpha- Mangostin belongs to a class of molecules called xanthones that have been shown to display antioxidant and anti-inflammatory activity, however, little attention has been given to its potential for cancer chemoprevention. Based on our preliminary results we have found that Mangostin can significantly reduce the tumor burden in athymic nude mice potentially throught the inhibition of kinases as identified in our screening process. To achieve this goal we are proposing two specific aims: (1) Determine the oral safety and tolerability of Mangostin in (2) Determine the efficacy of Mangostin in the TRAMP model when administered in food pellets. We believe that this proposal incorporates a more traditional drug development model that will be extremely valuable in creating preliminary data about the cancer chemopreventive potential of alpha-Mangostin for prostate cancer.
We believe that this proposal will be extremely valuable in provide preliminary data about the chemopreventive potential of Mangostin as well as the physicochemical and pharmacokinetic properties. Successful completion of this project will establish valuable data about the potential of Mangostin for prostate cancer chemoprevention. .
|Petiwala, Sakina M; Li, Gongbo; Ramaiya, Atulkumar et al. (2014) Pharmacokinetic characterization of mangosteen (Garcinia mangostana) fruit extract standardized to ?-mangostin in C57BL/6 mice. Nutr Res 34:336-45|
|Li, Gongbo; Petiwala, Sakina M; Pierce, Dana R et al. (2013) Selective modulation of endoplasmic reticulum stress markers in prostate cancer cells by a standardized mangosteen fruit extract. PLoS One 8:e81572|
|Ramaiya, Atulkumar; Li, Gongbo; Petiwala, Sakina M et al. (2012) Single dose oral pharmacokinetic profile of ?-mangostin in mice. Curr Drug Targets 13:1698-704|
|Johnson, Jeremy J; Petiwala, Sakina M; Syed, Deeba N et al. (2012) ýý-Mangostin, a xanthone from mangosteen fruit, promotes cell cycle arrest in prostate cancer and decreases xenograft tumor growth. Carcinogenesis 33:413-9|