Pharmacologic characterization of TBP1901, a prodrug form of aglycone curcumin, and CRISPR-Cas9 screen for therapeutic targets of aglycone curcumin.

Curcumin (aglycone curcumin) has antitumor properties in a variety of malignancies via the alteration of multiple cancer-related biological pathways; however, its clinical application has been hampered due to its poor bioavailability. To overcome this limitation, we have developed a synthesized curcumin ß-D-glucuronide sodium salt (TBP1901), a prodrug form of aglycone curcumin. In this study, we aimed to clarify the pharmacologic characteristics of TBP1901. In ß-glucuronidase (GUSB)-proficient mice, both curcumin ß-D-glucuronide and its active metabolite, aglycone curcumin, were detected in the blood after TBP1901 injection, whereas only curcumin ß-D-glucuronide was detected in GUSB-impaired mice, suggesting that GUSB plays a pivotal role in the conversion of TBP1901 into aglycone curcumin in vivo. TBP1901 itself had minimal antitumor effects in vitro, whereas it demonstrated significant antitumor effects in vivo. Genome-wide clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 screen disclosed the genes associated with NF-κB signaling pathway and mitochondria were among the highest hit. In vitro, aglycone curcumin inhibited NF-kappa B signaling pathways whereas it caused production of reactive oxygen species (ROS). ROS scavenger, N-acetyl-L-cysteine, partially reversed antitumor effects of aglycone curcumin. In summary, TBP1901 can exert antitumor effects as a prodrug of aglycone curcumin through GUSB-dependent activation.

Study protocol to determine the effects of highly absorbable oral curcumin on the indicators of cognitive functioning: a double-blind randomised controlled trial.

INTRODUCTION: Mild cognitive impairment (MCI) refers to a state in which cognitive functions, such as memory, have diminished but daily activities are largely unhampered. MCI is often overlooked but carries the risk of leading to development of dementia later. Curcumin is the main component of the natural herbal medicine turmeric. Curcumin is widely used as a health food and is an antioxidant that has anti-inflammatory and anti-amyloid actions. The current trial was designed to determine the effects of curcumin on indicators of cognitive functioning. METHODS AND ANALYSIS: The current trial will be a single-centre randomised placebo-controlled double-blind parallel group trial. The participants will be 60 members of the general public with potential MCI, based on dementia screening using the Japanese version of the Mini Mental State Examination (MMSE-J). The investigational health food used in this trial will be a recently developed preparation for highly absorbable oral curcumin. This trial will determine the effects of the highly absorbable oral curcumin (brand name: curcuRouge) on the indicators of cognitive functioning, including the scores obtained with the MMSE-J, which is an interview-based measure of cognitive functioning, and the blood biomarkers that have been reported to be associated with dementia. ETHICS AND DISSEMINATION: Informed written consent will be obtained from all the participants. The Ethical Review Board of the National Hospital Organization Kyoto Medical Center approved the study protocol. TRIAL REGISTRATION NUMBER: University Hospital Medical Information Network (UMIN000042471).

Curcumin ß-D-glucuronide exhibits anti-tumor effects on oxaliplatin-resistant colon cancer with less toxicity in vivo.

The NF-kappa B (NF-κB) pathway plays a pivotal role in tumor progression and chemoresistance, and its inhibition has been shown to suppress tumor growth in a variety of preclinical models. Recently, we succeeded in synthesizing a water-soluble injectable type of curcumin ß-D-glucuronide (CMG), which is converted into a free-form of curcumin by ß-glucuronidase in vivo. Herein, we aimed to clarify the efficacy, safety and pharmacokinetics of CMG in a xenograft mouse model. First, we confirmed that the presence of KRAS/TP53 mutations significantly increased the IC50 of oxaliplatin (L-OHP) and NF-κB activity in HCT116 cells in vitro. Then, we tested the efficacy of CMG in an HCT116 colon cancer xenograft mice model. CMG demonstrated superior anticancer effects compared to L-OHP in an L-OHP-resistant xenograft model. With regard to safety, significant bodyweight loss, severe myelosuppression and AST/ALT elevation were observed in L-OHP-treated mice, whereas none of these toxicity was noted in CMG-treated mice. The combination of CMG and L-OHP exhibited additive effects in these xenograft models without increasing toxicity. Pharmacokinetic analysis revealed that high levels of free-form curcumin were maintained in the tumor tissue after 48 hours following CMG administration, but it was not detected in other major organs, such as the heart, liver and spleen. Immunohistochemistry revealed reduced NF-κB activity in the tumor tissue extracted from CMG-treated mice compared with that from control mice. These results indicated that CMG could be a promising anticancer prodrug for treating colon cancer with minimal toxicity.

Preventive effect of curcumin and its highly bioavailable preparation on hearing loss induced by single or repeated exposure to noise: A comparative and mechanistic study.

We sought to determine the preventive effects of curcumin and its highly bioavailable preparation on noise-induced hearing loss in a novel murine model of permanent hearing loss developed by repeated exposure to noise. Upon exposure to noise (8-kHz octave band noise, 90 dB sound pressure level, 1 h), hearing ability was impaired in a temporary and reversible manner. During repeated noise exposure (1-h exposure per day, 5 days), there was a progressive increase in the auditory threshold shift at 12 and 20 kHz. The threshold shift persisted for at least 6 days after noise exposure. Oral administration of curcumin for 3 days before and each day during noise exposure significantly alleviated the hearing loss induced by repeated noise exposure. Curcumin abolished intranuclear translocation of nuclear factor-κB-p65 and generation of 4-hydroxynonenal-adducted proteins found in the cochlea after noise exposure. Theracurmin®, a highly absorbable and bioavailable preparation of curcumin, had strong preventive effects on hearing loss induced by repeated noise exposure. Together, these data suggest that curcumin exerts a preventive effect on noise-induced hearing loss and is therefore a good therapeutic candidate for preventing sensorineural hearing loss.

Colloidal submicron-particle curcumin exhibits high absorption efficiency-a double-blind, 3-way crossover study.

Curcumin is a major constituent of the spice turmeric and has various biological activities, including anticancer, antioxidant, and anti-inflammatory properties, as well as alcohol detoxification. However, because of its poor absorption efficiency, it is difficult for orally administered curcumin to reach blood levels sufficient to exert its bioactivities. To overcome this problem, several curcumin preparations with a drug-delivery system (DDS) have been developed to increase the bioavailability of curcumin after oral administration, and tested as functional foods and potential medical agents in humans. We have also produced capsules containing Theracurmin, curcumin dispersed with colloidal submicron-particles. To evaluate the absorption efficiency of three types of DDS curcumin, we performed a double-blind, 3-way crossover study. We compared plasma curcumin levels after the administration of Theracurmin and 2 other capsule types of curcumin with DDS, BCM-95 (micronized curcumin with turmeric essential oils) and Meriva (curcumin-phospholipid). Nine healthy subjects (male/female=5/4, age: 24-32 y old) were administered these 3 preparations of DDS curcumin, at commonly used dosages. Six capsules of Theracurmin, 1 capsule of BCM-95, and 2 capsules of Meriva contain 182.4 ± 1.0, 279.3 ± 10.7, and 152.5 ± 20.3 mg of curcumin, respectively. The maximal plasma curcumin concentration (0-24 h) of Theracurmin was 10.7 to 5.6 times higher than those of BCM-95 and Meriva, respectively. Moreover, the area under the blood concentration-time curve at 0-24 h was found to be 11.0- and 4.6-fold higher with Theracurmin than BCM-95 and Meriva, respectively. These data indicate that Theracurmin exhibits a much higher absorption efficiency than other curcumin DDS preparations.

Attenuation of indirect markers of eccentric exercise-induced muscle damage by curcumin.

PURPOSE: Polyphenolic curcumin is known to have potent anti-inflammatory effects; thus the present study investigated the hypothesis that curcumin ingestion would attenuate muscle damage after eccentric exercise. METHODS: Fourteen untrained young men (24 ± 1 years) performed 50 maximal isokinetic (120°/s) eccentric contractions of the elbow flexors of one arm on an isokinetic dynamometer and the same exercise with the other arm 4 weeks later. They took 150 mg of curcumin (theracurmin) or placebo (starch) orally before and 12 h after each eccentric exercise bout in a randomised, crossover design. Maximal voluntary contraction (MVC) torque of the elbow flexors, range of motion of the elbow joint, upper-arm circumference, muscle soreness, serum creatine kinase (CK) activity, and plasma interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) concentration were measured before, immediately after, and 24, 48, 72 and 96 h after each eccentric exercise. Changes in these variables over time were compared between curcumin and placebo conditions by two-way repeated measures ANOVA. RESULTS: MVC torque decreased smaller and recovered faster (e.g., 4 days post-exercise: -31 ± 13 % vs. -15 ± 15 %), and peak serum CK activity was smaller (peak: 7684 ± 8959 IU/L vs. 3398 ± 3562 IU/L) for curcumin than placebo condition (P < 0.05). However, no significant differences between conditions were evident for other variables, and no significant changes in IL-6 and TNF-α were evident after exercise. CONCLUSION: It is concluded that theracurmin ingestion attenuates some aspects of muscle damage such as MVC loss and CK activity increase.

Short-term effects of highly-bioavailable curcumin for treating knee osteoarthritis: a randomized, double-blind, placebo-controlled prospective study.

BACKGROUND: We previously developed a surface-controlled water-dispersible form of curcumin and named it Theracurmin(®) (Theracurmin; Theravalues, Tokyo, Japan). The area under the blood concentration-time curve of Theracurmin in humans was 27-fold higher than that of curcumin powder. We determined the clinical effects of orally administered Theracurmin in patients with knee osteoarthritis during 8 weeks of treatment. METHODS: Fifty patients with knee osteoarthritis of Kellgren-Lawrence grade II or III and who were aged more than 40 years were enrolled in this randomized, double-blind, placebo-controlled, prospective clinical study. Placebo or Theracurmin containing 180 mg/day of curcumin was administered orally every day for 8 weeks. To monitor adverse events, blood biochemistry analyses were performed before and after 8 weeks of each intervention. The patients' knee symptoms were evaluated at 0, 2, 4, 6, and 8 weeks by the Japanese Knee Osteoarthritis Measure, the knee pain visual analog scale (VAS), the knee scoring system of the Japanese Orthopedic Association, and the need for nonsteroidal anti-inflammatory drugs. RESULTS: At 8 weeks after treatment initiation, knee pain VAS scores were significantly lower in the Theracurmin group than in the placebo group, except in the patients with initial VAS scores of 0.15 or less. Theracurmin lowered the celecoxib dependence significantly more than placebo. No major side effects were observed with Theracurmin treatment. CONCLUSION: Theracurmin shows modest potential for the treatment of human knee osteoarthritis.

A novel drug delivery system of oral curcumin markedly improves efficacy of treatment for heart failure after myocardial infarction in rats.

Curcumin is an inhibitor of p300 histone acetyltransferase activity, which is associated with the deterioration of heart failure. We reported that native curcumin, at a dosage of 50 mg/kg, prevented deterioration of the systolic function in rat models of heart failure. To achieve more efficient oral pharmacological therapy against heart failure by curcumin, we have developed a novel drug delivery system (DDS) which markedly increases plasma curcumin levels. At the dosage of 0.5 mg/kg, DDS curcumin but not native curcumin restored left ventricular fractional shortening in post-myocardial infarction rats. Thus, our DDS strategy will be applicable to the clinical setting in humans.

A phase I/II study of gemcitabine-based chemotherapy plus curcumin for patients with gemcitabine-resistant pancreatic cancer.

PURPOSE: Curcumin, a plant-derived natural polyphenol, could be a promising anti-cancer drug and shows synergic effects with cytotoxic agents. We evaluated the safety and feasibility of combination therapy using curcumin with gemcitabine-based chemotherapy. METHODS: Gemcitabine-resistant patients with pancreatic cancer received 8 g oral curcumin daily in combination with gemcitabine-based chemotherapy. The primary endpoint was safety for phase I and feasibility of oral curcumin for phase II study. RESULTS: Twenty-one patients were enrolled. No dose-limiting toxicities were observed in the phase I study and oral curcumin 8 g/day was selected as the recommended dose for the phase II study. No patients were withdrawn from this study because of the intolerability of curcumin, which met the primary endpoint of the phase II study, and the median compliance rate of oral curcumin was 100% (Range 79-100%). Median survival time after initiation of curcumin was 161 days (95% confidence interval 109-223 days) and 1-year survival rate was 19% (4.4-41.4%). Plasma curcumin levels ranged from 29 to 412 ng/ml in five patients tested. CONCLUSIONS: Combination therapy using 8 g oral curcumin daily with gemcitabine-based chemotherapy was safe and feasible in patients with pancreatic cancer and warrants further investigation into its efficacy.