Resveratrol (3,4',5-trihydroxy-trans-stilbene) has been expected to ameliorate cancer and foster breakthroughs in cancer therapy. Despite thousands of preclinical studies on the anticancer activity of resveratrol, little progress has been made in translational research and clinical trials. Most studies have focused on its anticancer effects, cellular mechanisms, and signal transduction pathways in vitro and in vivo. In this review, we aimed to discern the causes that prevent resveratrol from being used in cancer treatment. Among the various limitations, poor pharmacokinetics and low potency seem to be the two main bottlenecks of resveratrol. In addition, resveratrol-induced nephrotoxicity in multiple myeloma patients hinders its further development as an anticancer drug. New insights and strategies have been proposed to accelerate the conversion of resveratrol from bench to bedside. In the interim, the most promising approach is to enhance the bioavailability of resveratrol with new formulations. Alternatively, more potent analogues of resveratrol could be developed to augment its anticancer potency. Given all the gaps mentioned, much work remains to be done. However, if remarkable progress can be made, resveratrol may finally be used for cancer therapy.

Signal transduction activator of transcription (STAT) 3 is a member of the STAT protein family which transduces intracellular and extracellular signals to the nucleus, controlling the expression of...

The aim of this study was to determine the maximum-tolerated dose (MTD), safety, pharmacokinetics, and pharmacodynamics of OPB-51602, an oral, direct signal transduction activator of transcription 3 (STAT3) inhibitor, in patients with refractory solid tumors. Three cohorts were studied: cohort A, a sequential dose escalation of OPB-51602 administered intermittently (days 1–14 every 21 days); cohort B, an expansion cohort evaluating the dose lower than the MTD; cohort C, evaluating continuous daily dosing. Fifty-one patients were studied at 2, 4, and 5 mg per day dosing. The MTD was 5 mg; first-cycle dose-limiting toxicities (DLTs) were grade 3 hyponatremia in one patient, and grade 3 dehydration in another. Intermittent dosing of both 2 and 4 mg doses were tolerable, and the recommended phase II dose was 4 mg. Cohort B investigated 4 mg intermittently, whereas cohort C investigated 4 mg continuously. Common toxicities included fatigue, nausea/vomiting, diarrhea, anorexia, and early-onset peripheral neuropathy. Drug-induced pneumonitis occurred in two patients in cohort C. Continuous dosing was associated with a higher incidence of peripheral neuropathy and a lower mean relative dose intensity, compared with intermittent dosing. Steady-state pharmacokinetics was characterized by high oral clearance, mean elimination half-life ranging from 44 to 61 h, and a large terminal-phase volume of distribution. An active metabolite, OPB-51822, accumulated to a greater extent than OPB-51602. Flow cytometry of peripheral blood mononuclear cells demonstrated pSTAT3 (Tyr⁷⁰⁵) inhibition following exposure. Two patients achieved partial responses at 5 mg intermittently and 4 mg continuously; both had epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC) with prior EGFR tyrosine kinase inhibitor exposure. OPB-51602 demonstrates promising antitumor activity, particularly in NSCLC. Its long half-life and poorer tolerability of continuous dosing, compared with intermittent dosing, suggest that less frequent dosing should be explored. NCT01184807.