A Phase I Study to Investigate the Safety, Tolerability and Pharmacokinetics of Napabucasin Combined with Sorafenib in Japanese Patients with Unresectable Hepatocellular Carcinoma.

BACKGROUND AND OBJECTIVE: For patients with advanced hepatocellular carcinoma (HCC), the standard of care for many years has been sorafenib. Preliminary data have suggested that the combination of the NAD(P)H:quinone oxidoreductase 1 bioactivatable agent napabucasin plus sorafenib may improve clinical outcomes in patients with HCC. In this phase I, multicenter, uncontrolled, open-label study, we evaluated napabucasin (480 mg/day) plus sorafenib (800 mg/day) in Japanese patients with unresectable HCC. METHODS: Adults with unresectable HCC and an Eastern Cooperative Oncology Group performance status of 0 or 1 were enrolled in a 3 + 3 trial design. The occurrence of dose-limiting toxicities was assessed through 29 days from the start of napabucasin administration. Additional endpoints included safety, pharmacokinetics, and preliminary antitumor efficacy. RESULTS: In the six patients who initiated treatment with napabucasin, no dose-limiting toxicities occurred. The most frequently reported adverse events were diarrhea (83.3%) and palmar-plantar erythrodysesthesia syndrome (66.7%), all of which were grade 1 or 2. The pharmacokinetic results for napabucasin were consistent with prior publications. The best overall response (per Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1) was stable disease in four patients. Using Kaplan-Meier methodology, the 6-month progression-free survival rate was 16.7% per RECIST 1.1 and 20.0% per modified RECIST for HCC. The 12-month overall survival rate was 50.0%. CONCLUSIONS: These findings confirm the viability of napabucasin plus sorafenib treatment, and there were no safety or tolerability concerns in Japanese patients with unresectable HCC. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02358395, registered on 9 February 2015.

Chitosan derivatives functionalized dual ROS-responsive nanocarriers to enhance synergistic oxidation-chemotherapy.

The efficient triggering of prodrug release has become a challengeable task for stimuli-responsive nanomedicine utilized in cancer therapy due to the subtle differences between normal and tumor tissues and heterogeneity. In this work, a dual ROS-responsive nanocarriers with the ability to self-regulate the ROS level was constructed, which could gradually respond to the endogenous ROS to achieve effective, hierarchical and specific drug release in cancer cells. In brief, DOX was conjugated with MSNs via thioketal bonds and loaded with ß-Lapachone. TPP modified chitosan was then coated to fabricate nanocarriers for mitochondria-specific delivery. The resultant nanocarriers respond to the endogenous ROS and release Lap specifically in cancer cells. Subsequently, the released Lap self-regulated the ROS level, resulting in the specific DOX release and mitochondrial damage in situ, enhancing synergistic oxidation-chemotherapy. The tumor inhibition Ratio was achieved to 78.49%. The multi-functional platform provides a novel remote drug delivery system in vivo.

Effect of Juglone against Pseudomonas syringae pv Actinidiae Planktonic Growth and Biofilm Formation.

Pseudomonas syringaepv Actinidiae (P. syringae) is a common pathogen causing plant diseases. Limoli proved that its strong pathogenicity is closely related to biofilm state. As a natural bacteriostatic agent with broad-spectrum bactericidal properties, juglone can be used as a substitute for synthetic bacteriostatic agents. To explore the antibacterial mechanism, this study was carried out to examine the inhibitory effect of juglone on cell membrane destruction, abnormal oxidative stress, DNA insertion and biofilm prevention of P. syringae. Results showed that juglone at 20 µg/mL can act against planktogenic P. syringae (107 CFU/mL). Specially, the application of juglone significantly damaged the permeability and integrity of the cell membrane of P. syringae. Additionally, juglone caused abnormal intracellular oxidative stress, and also embedded in genomic DNA, which affected the normal function of the DNA of P. syringae. In addition, environmental scanning electron microscope (ESEM) and other methods showed that juglone effectively restricted the production of extracellular polymers, and then affected the formation of the cell membrane. This study provided a possibility for the development and utilization of natural juglone in plants, especially P. syringae.

Napabucasin Drug-Drug Interaction Potential, Safety, Tolerability, and Pharmacokinetics Following Oral Dosing in Healthy Adult Volunteers.

Napabucasin is an orally administered reactive oxygen species generator that is bioactivated by the intracellular antioxidant nicotinamide adenine dinucleotide phosphate:quinone oxidoreductase 1. Napabucasin induces cell death in cancer cells, including cancer stem cells. This phase 1 study (NCT03411122) evaluated napabucasin drug-drug interaction potential for 7 cytochrome P450 (CYP) enzymes and the breast cancer resistance protein transporter/organic anion transporter 3. Healthy volunteers who tolerated napabucasin during period 1 received probe drugs during period 2, and in period 3 received napabucasin (240 mg twice daily; days 1-11) plus a phenotyping cocktail containing omeprazole (CYP2C19), caffeine (CYP1A2), flurbiprofen (CYP2C9), bupropion (CYP2B6), dextromethorphan (CYP2D6), midazolam (CYP3A) (all oral; day 6), intravenous midazolam (day 7), repaglinide (CYP2C8; day 8), and rosuvastatin (breast cancer resistance protein/organic anion transporter 3; day 9). Drug-drug interaction potential was evaluated in 17 of 30 enrolled volunteers. Napabucasin coadministration increased the area under the plasma concentration-time curve from time 0 extrapolated to infinity (geometric mean ratio [90% confidence interval]) of caffeine (124% [109.0%-141.4%]), intravenous midazolam (118% [94.4%-147.3%]), repaglinide (127% [104.7%-153.3%]), and rosuvastatin (213% [42.5%-1068.3%]) and decreased the area under the plasma concentration-time curve from time 0 extrapolated to infinity of dextromethorphan (71% [47.1%-108.3%]), bupropion (79% [64.6%-97.0%]), and hydroxybupropion (45% [15.7%-129.6%]). No serious adverse events/deaths were reported. Generally, napabucasin is not expected to induce/inhibit drug clearance to a clinically meaningful degree.

Mass balance and pharmacokinetics of an oral dose of 14 C-napabucasin in healthy adult male subjects.

This phase 1, open-label study assessed14 C-napabucasin absorption, metabolism, and excretion, napabucasin pharmacokinetics, and napabucasin metabolites (primary objectives); safety/tolerability were also evaluated. Eight healthy males (18-45 years) received a single oral 240-mg napabucasin dose containing ~100 µCi14 C-napabucasin. Napabucasin was absorbed and metabolized to dihydro-napabucasin (M1; an active metabolite [12.57-fold less activity than napabucasin]), the sole major circulating metabolite (median time to peak concentration: 2.75 and 2.25 h, respectively). M1 plasma concentration versus time profiles generally mirrored napabucasin; similar arithmetic mean half-lives (7.14 and 7.92 h, respectively) suggest M1 formation was rate limiting. Napabucasin systemic exposure (per Cmax and AUC) was higher than M1. The total radioactivity (TRA) whole blood:plasma ratio (AUClast : 0.376; Cmax : 0.525) indicated circulating drug-related compounds were essentially confined to plasma. Mean TRA recovery was 81.1% (feces, 57.2%; urine, 23.8%; expired air, negligible). Unlabeled napabucasin and M1 recovered in urine accounted for 13.9% and 11.0% of the dose (sum similar to urine TRA recovered); apparent renal clearance was 8.24 and 7.98 L/h. No uniquely human or disproportionate metabolite was quantified. Secondary glucuronide and sulfate conjugates were common urinary metabolites, suggesting napabucasin was mainly cleared by reductive metabolism. All subjects experienced mild treatment-emergent adverse events (TEAEs), the majority related to napabucasin. The most commonly reported TEAEs were gastrointestinal disorders. There were no clinically significant laboratory, vital sign, electrocardiogram, or physical examination changes. Napabucasin was absorbed, metabolized to M1 as the sole major circulating metabolite, and primarily excreted via feces. A single oral 240-mg dose was generally well tolerated.

Functional Investigation of Solute Carrier Family 35, Member F2, in Three Cellular Models of the Primate Blood-Brain Barrier.

Understanding the mechanisms of drug transport across the blood-brain barrier (BBB) is an important issue for regulating the pharmacokinetics of drugs in the central nervous system. In this study, we focused on solute carrier family 35, member F2 (SLC35F2), whose mRNA is highly expressed in the BBB. SLC35F2 protein was enriched in isolated mouse and monkey brain capillaries relative to brain homogenates and was localized exclusively on the apical membrane of MDCKII cells and brain microvascular endothelial cells (BMECs) differentiated from human induced pluripotent stem cells (hiPS-BMECs). SLC35F2 activity was assessed using its substrate, YM155, and pharmacological experiments revealed SLC35F2 inhibitors, such as famotidine (half-maximal inhibitory concentration, 160 µM). Uptake of YM155 was decreased by famotidine or SLC35F2 knockdown in immortalized human BMECs (human cerebral microvascular endothelial cell/D3 cells). Furthermore, famotidine significantly inhibited the apical (A)-to-basal (B) transport of YM155 in primary cultured monkey BMECs and hiPS-BMECs. Crucially, SLC35F2 knockout diminished the A-to-B transport and intracellular accumulation of YM155 in hiPS-BMECs. By contrast, in studies using an in situ brain perfusion technique, neither deletion of Slc35f2 nor famotidine reduced brain uptake of YM155, even though YM155 is a substrate of mouse SLC35F2. YM155 uptake was decreased significantly by losartan and naringin, inhibitors for the organic anion transporting polypeptide (OATP) 1A4. These findings suggest SLC35F2 is a functional transporter in various cellular models of the primate BBB that delivers its substrates to the brain and that its relative importance in the BBB is modified by differences in the expression of OATPs between primates and rodents. SIGNIFICANCE STATEMENT: This study demonstrated that SLC35F2 is a functional drug influx transporter in three different cellular models of the primate blood-brain barrier (i.e., human cerebral microvascular endothelial cell/D3 cells, primary cultured monkey BMECs, and human induced pluripotent stem-BMECs) but has limited roles in mouse brain. SLC35F2 facilitates apical-to-basal transport across the tight cell monolayer. These findings will contribute to the development of improved strategies for targeting drugs to the central nervous system.

Enhanced antitumor efficacy of lapachol-loaded nanoemulsion in breast cancer tumor model.

Lapachol (LAP) is a natural compound with various biological properties, including anticancer activity. However, its clinical application is limited due to the low aqueous solubility and potential adverse side effects. Nanoemulsions are drug delivery systems that can assist in the administration of hydrophobic drugs, increasing their bioavailability and protecting from degradation. Thus, this study aimed to prepare a LAP-loaded nanoemulsion (NE-LAP), and evaluate its antitumor activity. For this purpose, the nanoemulsion was prepared using a hot homogenization method and characterized morphologically by cryogenic transmission electron microscopy (cryo-TEM). Mean diameter, polydispersity index, and zeta potential was evaluated by DLS, encapsulation efficiency was measured by HPLC. Moreover, the short-term storage stability, the drug release and hemolysis in vitro was determined. Additionally, pharmacokinetic, toxicology and toxicity properties of99mTc-NE-LAP were evaluated in a breast cancer (4T1) tumor model. The cryo-TEM showed spherical globules, and the physicochemical characterization of NE-LAP showed a homogeneous stable nanoemulsion with a mean diameter of ∼170 nm, zeta potential of around -20 mV, and encapsulation greater than 85 %. In vitro studies validated that encapsulation did not impair the cytotoxicity activity of LAP. The nanoemulsion was successfully radiolabeled and 99mTc-NE-LAP showed prolonged blood circulation and tumor affinity was confirmed by tumor-to-muscle ratio. Moreover, NE-LAP showed higher antitumor activity than the free drug and the treatment did not result in any signs of toxicity. Therefore, these findings suggest that NE-LAP can be considered an effective strategy for cancer treatment.

Ultrasound Combined with Core Cross-Linked Nanosystem for Enhancing Penetration of Doxorubicin Prodrug/Beta-Lapachone into Tumors.

BACKGROUND: Nanosized drug delivery systems (NDDSs) have shown excellent prospects in tumor therapy. However, insufficient penetration of NDDSs has significantly impeded their development due to physiological instability and low passive penetration efficiency. METHODS: Herein, we prepared a core cross-linked pullulan-modified nanosized system, fabricated by visible-light-induced diselenide bond cross-linked method for transporting ß-Lapachone and doxorubicin prodrug (boronate-DOX, BDOX), to improve the physiological stability of the NDDSs for efficient passive accumulation in tumor blood vessels (ß-Lapachone/BDOX-CCS). Additionally, ultrasound (US) was utilized to transfer ß-Lapachone/BDOX-CCS around the tumor vessel in a relay style to penetrate the tumor interstitium. Subsequently, ß-Lapachone enhanced ROS levels by overexpressing NQO1, resulting in the transformation of BDOX into DOX. DOX, together with abundant levels of ROS, achieved synergistic tumor therapy. RESULTS: In vivo experiments demonstrated that ultrasound (US) + cross-linked nanosized drug delivery systems (ß-Lapachone/BDOX-CCS) group showed ten times higher DOX accumulation in the tumor interstitium than the non-cross-linked (ß-Lapachone/BDOX-NCS) group. CONCLUSION: Thus, this strategy could be a promising method to achieve deep penetration of NDDSs into the tumor.

Bifunctional Naphtho[2,3-d][1,2,3]triazole-4,9-dione Compounds Exhibit Antitumor Effects In Vitro and In Vivo by Inhibiting Dihydroorotate Dehydrogenase and Inducing Reactive Oxygen Species Production.

Human dihydroorotate dehydrogenase (hDHODH) is an attractive target for cancer therapy. Based on its crystal structure, we designed and synthesized a focused compound library containing the structural moiety of 1,4-benzoquinone, which possesses reactive oxygen species (ROS) induction capacity. Compound 3s with a naphtho[2,3-d][1,2,3]triazole-4,9-dione scaffold exhibited inhibitory activity against hDHODH. Further optimization led to compounds 11k and 11l, which inhibited hDHODH activity with IC50 values of 9 and 4.5 nM, respectively. Protein-ligand cocrystal structures clearly depicted hydrogen bond and hydrophobic interactions of 11k and 11l with hDHODH. Compounds 11k and 11l significantly inhibited leukemia cell and solid tumor cell proliferation and induced ROS production, mitochondrial dysfunction, apoptosis, and cell cycle arrest. Nanocrystallization of compound 11l displayed significant in vivo antitumor effects in the Raji xenograft model. Overall, this study provides a novel bifunctional compound 11l with hDHODH inhibition and ROS induction efficacy, which represents a promising anticancer lead worthy of further exploration.

Phase 1 study of napabucasin, a cancer stemness inhibitor, in patients with advanced solid tumors.

PURPOSE: Napabucasin is a cancer stemness inhibitor that targets a number of oncogenic pathways, including signal transducer and activator of transcription 3 (STAT3). Phase 1/2 studies suggest tolerability and anti-tumor activity in various types of cancer; a Phase 3 study of napabucasin plus standard therapy in colorectal cancer is ongoing. This is a Phase 1 dose-escalation study in patients with advanced solid tumors, and the first study of napabucasin in Japanese patients. METHODS: Patients received napabucasin 480, 960, or 1440 mg daily in 28-day cycles until disease progression or intolerable toxicity. Primary objectives were to determine dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), and the pharmacokinetic (PK) profile of napabucasin. Blood samples were taken for PK analysis on Days 1, 2, 8, and 15 of Cycle 1, and Days 29 and 30 of Cycle 2. Secondary objectives were to assess napabucasin antitumor activity, and the relationship between biomarkers and antitumor activity. JapicCTI-No: JapicCTI-132152. RESULTS: Enrolled were 14 patients (480 mg [n = 3], 960 mg [n = 4], 1440 mg [n = 7]). One patient experienced a DLT (Grade 3, anorexia). MTD was 1440 mg/day. Most common drug-related adverse events were diarrhea (n = 9), nausea (n = 4), vomiting (n = 3), and anorexia (n = 3). Napabucasin showed a similar PK profile to previous studies and no abnormal accumulation was observed. Following treatment, two patients had stable disease; the remaining 12 had progressive disease. CONCLUSION: Napabucasin was well-tolerated at doses up to 1440 mg/day in Japanese patients with advanced solid tumors; the PK profile was comparable to that reported previously.

Naphthoquinones, benzoquinones, and anthraquinones: Molecular docking, ADME and inhibition studies on human serum paraoxonase-1 associated with cardiovascular diseases.

Paraoxonase-1 (PON1) has essential roles such as protecting low-density lipoprotein against detoxification and oxidation of highly toxic compounds. Quinones are a class of compounds and a type of plant-derived secondary metabolites. Here, PON1 was purified using very simple methods and evaluation of the interactions between the enzyme and some quinones. It was found that these quinones displayed effective inhibitor properties for PON1 with the IC50 values in the range of 3.27-82.90 µM and the K i values in the range of 2.50 ± 0.65 to 30.90 ± 7.20 µM. These quinones displayed distinct inhibition mechanisms. It was determined that except for 5-hydroxy-2-methyl-1,4-naphthoquinone and 2-methyl-1,4-naphthoquinone all quinones exhibit competitive inhibition effects. Also, molecular docking and in silico ADME studies were performed. Usage of drugs including quinone derivatives in structure with biological activity would be hazardous in some cases.

Microbiota changes associated with ADNP deficiencies: rapid indicators for NAP (CP201) treatment of the ADNP syndrome and beyond.

Activity-dependent neuroprotective protein (ADNP) and its protein snippet NAP (drug candidate CP201) regulate synapse formation and cognitive as well as behavioral functions, in part, through microtubule interaction. Given potential interactions between the microbiome and brain function, we now investigated the potential effects of the ADNP-deficient genotype, mimicking the ADNP syndrome on microbiota composition in the Adnp+/- mouse model. We have discovered a surprising robust sexually dichotomized Adnp genotype effect and correction by NAP (CP201) as follows. Most of the commensal bacterial microbiota tested were affected by the Adnp genotype and corrected by NAP treatment in a male sex-dependent manner. The following list includes all the bacterial groups tested-labeled in bold are male Adnp-genotype increased and corrected (decreased) by NAP. (1) Eubacteriaceae (EubV3), (2) Enterobacteriaceae (Entero), (3) Enterococcus genus (gEncocc), (4) Lactobacillus group (Lacto), (5) Bifidobacterium genus (BIF), (6) Bacteroides/Prevotella species (Bac), (7) Clostridium coccoides group (Coer), (8) Clostridium leptum group (Cluster IV, sgClep), and (9) Mouse intestinal Bacteroides (MIB). No similarities were found between males and females regarding sex- and genotype-dependent microbiota distributions. Furthermore, a female Adnp+/- genotype associated decrease (contrasting male increase) was observed in the Lactobacillus group (Lacto). Significant correlations were discovered between specific bacterial group loads and open-field behavior as well as social recognition behaviors. In summary, we discovered ADNP deficiency associated changes in commensal gut microbiota compositions, a sex-dependent biomarker for the ADNP syndrome and beyond. Strikingly, we discovered rapidly detected NAP (CP201) treatment-dependent biomarkers within the gut microbiota.

Shape mediated splenotropic delivery of buparvaquone loaded solid lipid nanoparticles.

Buparvaquone (BPQ)-loaded asymmetric solid lipid nanoparticles (SLN) prepared by a modified nanoprecipitation method were evaluated for splenotropic drug delivery. BPQ SLN exhibited an average particle size of 650.28 ± 6.75 nm with polydispersity index ≤ 0.3, entrapment efficiency of 96.57 ± 0.190%, and drug loading of 24.63 ± 0.042%. Scanning electron microscopy (SEM) revealed elongated particles with flattened and rounded edges. Aspect ratio, an important determinant of asymmetricity of the BPQ SLN, measured as the ratio of average length (1143 ± 0.083 nm) to width (419 ± 0.031 nm) was found to be 2.727 ± 0.19. The hemolytic potential of 10.86 ± 0.04% and good serum stability suggested feasibility for intravenous administration. 99mTc-labeled BPQ SLN revealed high radiolabeling efficiency (> 95%) and good stability. Intravenous administration in mice revealed > 75% accumulation in the reticuloendothelial system organs. The percent radioactivity per gram of organ was in the order spleen > kidney > lungs > liver > lymph nodes, with high splenic accumulation and significantly lower concentration in the liver. An astoundingly high spleen/liver ratio with a maximum of 11.94 ± 1.37 at 3 h, which confirmed high splenic uptake is attributed to Kupffer cell bypass. Other factors contributing to splenotropy are the rigidity and the low molecular weight of the lipid in the BPQ SLN which enabled translocation of the particles into the splenic pulp. Our study proposes asymmetric BPQ SLN as a promising splenotropic delivery system for improved efficacy in theileriosis, a spleen resident infection.

Echinochrome A Reduces Colitis in Mice and Induces In Vitro Generation of Regulatory Immune Cells.

Echinochrome A (Ech A), a natural pigment extracted from sea urchins, is the active ingredient of a marine-derived pharmaceutical called 'histochrome'. Since it exhibits several biological activities including anti-oxidative and anti-inflammatory effects, it has been applied to the management of cardiac injury and ocular degenerative disorders in Russia and its protective role has been studied for other pathologic conditions. In the present study, we sought to investigate the therapeutic potential of Ech A for inflammatory bowel disease (IBD) using a murine model of experimental colitis. We found that intravenous injection of Ech A significantly prevented body weight loss and subsequent lethality in colitis-induced mice. Interestingly, T cell proliferation was significantly inhibited upon Ech A treatment in vitro. During the helper T (Th) cell differentiation process, Ech A stimulated the generation regulatory T (Treg) cells that modulate the inflammatory response and immune homeostasis. Moreover, Ech A treatment suppressed the in vitro activation of pro-inflammatory M1 type macrophages, while inducing the production of M2 type macrophages that promote the resolution of inflammation and initiate tissue repair. Based on these results, we suggest that Ech A could provide a beneficial impact on IBD by correcting the imbalance in the intestinal immune system.

Tumor-Specific Expansion of Oxidative Stress by Glutathione Depletion and Use of a Fenton Nanoagent for Enhanced Chemodynamic Therapy.

Amplifying intracellular oxidative stress effectively destroys cancer cells. In addition, iron-mediated Fenton reaction converts endogenous H2O2 to produce hypertoxic hydroxyl radical (•OH), resulting in irreversible oxidative damage to combat tumor cells. This method is known as chemodynamic therapy (CDT). Overexpressed glutathione (GSH) in tumor cells efficiently scavenges •OH, significantly reducing the curative effects of CDT. To overcome this challenge and enhance intracellular oxidative stress, iron oxide nanocarriers loaded with ß-lapachone (Lapa) drugs (Fe3O4-HSA@Lapa) were constructed and had both Fenton-like agents and GSH depletion properties to amplify intracellular oxidative stress. Release of Lapa selectively increases tumor site-specific generation of H2O2 via NAD(P)H: quinone oxidoreductase 1 (NQO1) catalysis. Subsequently, the iron ions released from the ionization of Fe3O4 in the acidic environment selectively convert H2O2 into highly toxic •OH by Fenton reaction, dramatically improving CDT with minimal systemic toxicity due to low NQO1 expression in normal tissues. Meanwhile, released Lapa consumes GSH in the tumor, amplifying oxidative stress and enhancing the efficacy of CDT. Designed Fe3O4-HSA@Lapa nanoparticles (NPs) exhibit perfect targeting capability, prolonged blood circulation, and increased tumor accumulation. Furthermore, Fe3O4-HSA@Lapa NPs effectively enhance the inhibition of tumor growth and reduce the side effects of anticancer drugs. This work establishes a remarkably enhanced tumor-selective CDT against NQO1-overexpressing tumors by significantly inducing intratumoral oxidative stress with minimal side effects.

Tailored Design of an ROS-Responsive Drug Release Platform for Enhanced Tumor Therapy via "Sequential Induced Activation Processes".

The reactive oxygen species (ROS)-responsive intelligent drug delivery system has developed rapidly in recent years. However, because of the low concentration of ROS in most types of tumor cells, it is not possible to rapidly and effectively stimulate the drug delivery system to release the active drug. Here, we introduced "sequential induced activation processes" for efficient tumor therapy by designing a new ROS-responsive drug release platform. ß-Lapachone, a positively charged nitrogen mustard (NM) prodrug, and two diblock molecules (mPEG-AcMH and PAsp-AcMH) are self-assembled to form prodrug primary micelles, which are further aggregated into nanoparticles that facilitate drug codelivery. When administered by intravenous injection, the nanoparticles reach the tumor site and enter the tumor cells by endocytosis. The ß-lapachone released in the tumor cells induces a large amount of H2O2, and the ROS-responsive NM prodrug is activated to form activated NM, quinone methide, and boric acid under the induction of H2O2. The activated NM leads to tumor cell apoptosis.

A Phase I Study of Napabucasin Plus Paclitaxel for Japanese Patients With Advanced/Recurrent Gastric Cancer.

AIM: To report results from the first phase I study of napabucasin plus paclitaxel in Japanese patients with pre-treated unresectable/recurrent gastric cancer. PATIENTS AND METHODS: Patients received napabucasin (480 mg bid) plus paclitaxel [80 mg/m2 on days 3, 10 and 17 (cycles 1 and 2) and on days 1, 8 and 15 (cycle 3 and subsequent cycles)] until disease progression or unacceptable toxicity. Primary objectives were tolerability, safety and pharmacokinetics of napabucasin plus paclitaxel. Trial registration ID: JapicCTI-142420. RESULTS: Six patients were enrolled. Paclitaxel had a minimal effect on napabucasin pharmacokinetics and median plasma paclitaxel concentrations were similar in combination and monotherapy. No dose-limiting toxicities were observed. There were no grade 4/5 adverse events. Partial response, stable disease and progressive disease were reported in two patients each. CONCLUSION: Napabucasin plus paclitaxel was well-tolerated in Japanese patients with gastric cancer.

Anti-hyperglycemic and anti-hyperlipidemic effects of rhinacanthins-rich extract from Rhinacanthus nasutus leaves in nicotinamide-streptozotocin induced diabetic rats.

Rhinacanthus nasutus has traditionally been used in the treatment of various disorders including diabetes mellitus. Rhinacanthins-rich extract (RRE) is a semipurified R. nasutus leaf extract that contains 60% w/w of rhinacanthin-C (RC) obtained by a green extraction process. The purpose of this study was to investigate the anti-hyperglycemic and anti-hyperlipidemic activity of RRE (15 mg/kg equivalent to RC content) in comparison to its marker compound RC (15 mg/kg) and the standard drug glibenclamide (Glb) (600 µg/kg) in nicotinamide-streptozotocin induced diabetic rats for 28 days. In addition, the in silico pharmacokinetic and toxicity analysis of RC was also performed. RRE, RC and Glb significantly reduced the FBG, HbA1c and food/water intake while increasing the insulin level and body weight in diabetic rats without affecting the normal rats. The serum lipid, liver and kidney biomarkers were markedly normalized by RRE, RC and Glb in diabetic rats without affecting the normal rats. Moreover, the histopathology of the pancreas revealed that RRE, RC and Glb evidently restored the islets of Langerhans in diabetic rats. The overall results indicated that RRE has equivalent antidiabetic potential to that of RC. Moreover, the in silico pharmacokinetic and toxicity analysis predicts that RC is orally non-toxic, non-carcinogenic and non-mutagenic with a decent bioavailability. The undertaken study suggests that RRE could be used as an effective natural remedy in the treatment of diabetes.

Technetium-99m-labeled lapachol as an imaging probe for breast tumor identification. / Lapachol marcado con tecnecio 99m como sonda de imágenes para la identificación de tumores de mama.

OBJECTIVE: Breast cancer is a health problem worldwide with high incidence and mortality rates. It is well known that the development of more sensitive and specific diagnostic methods is of great importance since an early diagnosis is essential to successfully treat tumors. Lapachol is a natural compound, belonging to the naphthoquinone group that has been widely used in traditional medicine to treat various illnesses, including cancer. The aim of this study was to evaluate technetium-99m (99mTc) labeled lapachol as an imaging probe for breast cancer identification. METHODS: To achieve this purpose, lapachol was labeled with 99mTc, radiochemical purity and in vitro stability were determined. Blood clearance, in healthy mice, and biodistribution, in 4T1 tumor-bearing mice, were also evaluated. RESULTS: Lapachol was successfully labeled with 99mTc, with high values of radiochemical yield (95.9±3.4%). In vitro stability showed that the radiolabeled complex remained stable for up to 24h, with values above 90% for both saline and plasma (95.6±3.6% and 96.4±1.7%, respectively). The radiolabeled complex decays in a biphasic manner, with a half-life of distribution and elimination equal to 3.3 and 50.0min, respectively. Biodistribution and scintigraphic images showed high uptake in organs of excretion (kidneys, liver, and intestine). It could be also noted that tumor uptake was higher than the muscle at all time points. Tumor-to-muscle ratio reaches ∼4.5 at 24h after administration. CONCLUSION: These findings suggest that 99mTc-lapachol can be a potential diagnostic agent for breast tumors.

Design, synthesis and biological evaluation of fused naphthofuro[3,2-c] quinoline-6,7,12-triones and pyrano[3,2-c]quinoline-6,7,8,13-tetraones derivatives as ERK inhibitors with efficacy in BRAF-mutant melanoma.

Approximately 60% of human cancers exhibit enhanced activity of ERK1 and ERK2, reflecting their multiple roles in tumor initiation and progression. Acquired drug resistance, especially mechanisms associated with the reactivation of the MAPK (RAF/MEK/ERK) pathway represent a major challenge to current treatments of melanoma and several other cancers. Recently, targeting ERK has evolved as a potentially attractive strategy to overcome this resistance. Herein, we report the design and synthesis of novel series of fused naphthofuro[3,2-c]quinoline-6,7,12-triones 3a-f and pyrano[3,2-c]quinoline-6,7,8,13-tetraones 5a,b and 6, as potential ERK inhibitors. New inhibitors were synthesized and identified by different spectroscopic techniques and X-ray crystallography. They were evaluated for their ability to inhibit ERK1/2 in an in vitro radioactive kinase assay. 3b and 6 inhibited ERK1 with IC50s of 0.5 and 0.19 µM, and inhibited ERK2 with IC50s of 0.6 and 0.16 µM respectively. Kinetic mechanism studies revealed that the inhibitors are ATP-competitive inhibitors where 6 inhibited ERK2 with a Ki of 0.09 µM. Six of the new inhibitors were tested for their in vitro anticancer activity against the NCI-60 panel of tumor cell lines. Compound 3b and 6 were the most potent against most of the human tumor cell lines tested. Moreover, 3b and 6 inhibited the proliferation of the BRAF mutant A375 melanoma cells with IC50s of 3.7 and 0.13 µM, respectively. In addition, they suppressed anchorage-dependent colony formation. Treatment of the A375 cell line with 3b and 6 inhibited the phosphorylation of ERK substrates p-90RSK and ELK-1 and induced apoptosis in a dose dependent manner. Finally, a molecular docking study showed the potential binding mode of 3b and 6 within the ATP catalytic binding site of ERK2.