Sulforaphane for the chemoprevention of bladder cancer: molecular mechanism targeted approach

Abstract

The clinical course for both early and late stage Bladder Cancer (BC) continues to be characterized by significant patient burden due to numerous occurrences and recurrences requiring frequent surveillance strategies, intravesical drug therapies, and even more aggressive treatments in patients with locally advanced or metastatic disease. For these reasons, BC is also the most expensive cancer to treat. Fortunately, BC offers an excellent platform for chemoprevention interventions with potential to optimize the systemic and local exposure of promising agents to the bladder mucosa. However, other than smoking cessation, there is a paucity of research that systematically examines agents for chemoprevention of bladder cancers. Adopting a systematic, molecular-mechanism based approach, the goal of this review is to summarize epidemiological, in vitro, and preclinical studies, including data regarding the safety, bioavailability, and efficacy of agents evaluated for bladder cancer chemoprevention. Based on the available studies, phytochemicals, specifically isothiocyanates such as sulforaphane, present in Brassicaceae or “cruciferous” vegetables in the precursor form of glucoraphanin are: (a) available in standardized formulations; (b) bioavailable- both systemically and in the bladder; (c) observed to be potent inhibitors of BC carcinogenesis through multiple mechanisms; and (d) without toxicities at these doses. Based on available evidence from epidemiological, in vitro, preclinical, and early phase trials, phytochemicals, specifically isothiocyanates (ITCs) such as sulforaphane (SFN) represent a promising potential chemopreventitive agent in bladder cancer.

Cruciferous Vegetables, Isothiocyanates, and Bladder Cancer Prevention

“…A wide body of evidence suggests that isothiocyanates possess potent anticancer activity via induction of apoptosis through several distinct molecular mechanisms of action that include targeting the Keap‐1‐ and Nrf2‐dependent adaptive stress response, inhibition of phase I enzymes (i.e., cytochrome p450), interfering with inflammatory and pro‐growth/‐survival intracellular signaling pathways, and through disruption of mitochondrial function, reviewed extensively in refs. [].…”

“…A well‐defined isothiocyanate anticancer mechanism of action, which may modulate bladder cancer initiation, involves inhibition of phase I enzymes (i.e., cytochrome p450) and the induction of phase II enzymes, such as GST, quinone reductase (QR), and NAD(P)H:quinone oxidoreductase‐1 (NOQ1), reviewed in ref. []. Phase I enzymes cause carcinogenic compounds to become more hydrophilic through numerous oxidation, reduction, and hydrolysis reactions, causing increased reactivity and DNA damage .…”

The Glucosinolates, A Sulphur Glucoside Family of Mustard Phytochemicals With Diverse Biomedical Application

“…Leukemia [87,124,[175][176][177][178][179] Prostate cancer [91,95,[180][181][182] non-small cell lung cancer cells [107,183,184] Pancreatic cancer [165,[185][186][187] Breast cancer [92, 93, 101-103, 105, 108, 109, 188-195] Bladder cancer [169,[196][197][198][199][200][201] Ovarian cancer [99] HepG2 Carcinoma Cells [202][203][204][205][206] Gastric cancer [207,208] Squamous cell carcinoma [209,210] Nasopharangeal cancer [211] Melanoma [212] Glioma [173,[213][214][215] Colon cancer [110,216,217] Lung cancer [218,219]...…”

The role of phytochemicals in modulating intrinsic human cellular defence processes

“…In the urinary bladder, concentration of SFN metabolites in the urine for extended time periods prior to voiding may explain the observed cytoprotective effects of SFN in this organ. 628 Myzak et al 629 report that HDAC inhibition was apparent in murine colonic mucosa and peripheral mononuclear cells, suggesting that dietary SFN is capable of inhibiting HDAC in vivo. It is worth noting that in general, HDAC inhibitors exhibit greater effects on cancer cells than on normal cells, 630 raising the possibility that such differential effects may provide an opportunity to utilise SFN in cancer therapy as well as in prevention.…”

“…SFN as a therapy in the context of bladder cancer prevention is discussed in some detail in a recent review paper. 628 Overall, review of the published literature on SFN shows that the doses required for Nrf2 induction are lower than those for HDAC inhibition and a number of other putative cytoprotective processes. 157 When considering the higher dose levels, one must consider the potential for toxicity.…”