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Supplementary Figure 5 from Novel STAT3 Phosphorylation Inhibitors Exhibit Potent Growth-Suppressive Activity in Pancreatic and Breast Cancer Cells

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BACKGROUND: Factor VIIc, fibrinogen, and plasminogen activator inhibitor 1 (PAI-1) are cardiovascular disease (CVD) risk factors and are modulated, in part, by fat type and amount. OBJECTIVE: We evaluated fat type and amount on the primary outcomes: factor VIIc, fibrinogen, and PAI-1. METHODS: In the Dietary Effects on Lipoproteins and Thrombogenic Activity (DELTA) Trial, 2 controlled crossover feeding studies evaluated substituting carbohydrate or MUFAs for SFAs. Study 1: healthy participants (n = 103) were provided with (8 wk) an average American diet [AAD; designed to provide 37% of energy (%E) as fat, 16% SFA], a Step 1 diet (30%E fat, 9% SFA), and a diet low in SFA (Low-Sat; 26%E fat, 5% SFA). Study 2: participants (n = 85) at risk for CVD and metabolic syndrome (MetSyn) were provided with (7 wk) an AAD, a step 1 diet, and a high-MUFA diet (designed to provide 37%E fat, 8% SFA, 22% MUFA). RESULTS: Study 1: compared with AAD, the Step 1 and Low-Sat diets decreased mean factor VIIc by 1.8% and 2.6% (overall P = 0.0001), increased mean fibrinogen by 1.2% and 2.8% (P = 0.0141), and increased mean square root PAI-1 by 0.0% and 6.0% (P = 0.0037), respectively. Study 2: compared with AAD, the Step 1 and high-MUFA diets decreased mean factor VIIc by 4.1% and 3.2% (overall P

Prime-boost vaccination with recombinant (r) vaccinia(V)-CEA(6D)-TRICOM (triad of co-stimulatory molecules B7.1, ICAM-1 and LFA-3) and rFowlpox(F)-CEA(6D)-TRICOM infect antigen-presenting cells and direct expression of co-stimulatory molecules. We hypothesized that co-administration of vaccine with GM-CSF and interferon alpha (IFN-α) would have efficacy in CEA-expressing cancers. Patients with CEA-expressing cancers received the rV-CEA(6D)-TRICOM vaccine subcutaneously (s.c.) on day 1 followed by GM-CSF s.c. to the injection site on days 1-4. In Cycle 1, patients received thrice weekly s.c. injections of IFN-α-2b the week after rV-CEA(6D)-TRICOM. In Cycles 2-4, patients received thrice weekly s.c. injections of IFN-α-2b the same week that rF-CEA(6D)-TRICOM was given. The first cohort received no IFN followed by dose escalation of IFN-α in subsequent cohorts. Thirty-three patients were accrued (mean 59.8 years). Grade 3 toxicities included fatigue and hyperglycemia. Grade 4-5 adverse events (unrelated to treatment) were confusion (1), elevated aspartate transaminase (AST)/alanine transaminase (ALT) (1), and sudden death (1). No patients had a partial response, and eight patients exhibited stable disease of ≥3 months. Median progression-free survival and overall survival (OS) were 1.8 and 6.3 months, respectively. Significantly higher serum CD27 levels were observed after vaccine therapy (p = 0.006 post 1-2 cycles, p = 0.003 post 3 cycles, p = 0.03 post 4-7 cycles) and 42 % of patients assayed developed CEA-specific T cell responses. Pre-treatment levels of myeloid-derived suppressor cells correlated with overall survival (p = 0.04). Administration of IFN-α led to significantly increased OS (p = 0.02) compared to vaccine alone. While the vaccine regimen produced no clinical responses, IFN-α administration was associated with improved survival.

Aim To conduct an integrative review to examine evidence of pain and associated symptoms in adult (≥21 years of age), postcraniotomy, brain tumour patients hospitalized on intensive care units. Background Healthcare providers believe craniotomies are less painful than other surgical procedures. Understanding how postcraniotomy pain unfolds over time will help inform patient care and aid in future research and policy development. Design Systematic literature search to identify relevant literature. Information abstracted using the Theory of Unpleasant Symptoms’ concepts of influencing factors, symptom clusters and patient performance. Inclusion criteria were indexed, peer-reviewed, full-length, English-language articles. Keywords were ‘traumatic brain injury’, ‘pain, post-operative’, ‘brain injuries’, ‘postoperative pain’, ‘craniotomy’, ‘decompressive craniectomy’ and ‘trephining’. Data sources Medline, OVID, PubMed and CINAHL databases from 2000–2014. Review method Cooper's five-stage integrative review method was used to assess and synthesize literature. Results The search yielded 115 manuscripts, with 26 meeting inclusion criteria. Most studies were randomized, controlled trials conducted outside of the United States. All tested pharmacological pain interventions. Postcraniotomy brain tumour pain was well-documented and associated with nausea, vomiting and changes in blood pressure, and it impacted the patient's length of hospital stay, but there was no consensus for how best to treat such pain. Conclusion The Theory of Unpleasant Symptoms provided structure to the search. Postcraniotomy pain is experienced by patients, but associated symptoms and impact on patient performance remain poorly understood. Further research is needed to improve understanding and management of postcraniotomy pain in this population.

Introduction Persistent musculoskeletal pain is a prevalent, disabling, and often undertreated condition. This paper examines the acceptability of a telecare intervention for this condition. Methods The Stepped Care to Optimize Pain Care Effectiveness (SCOPE) intervention couples automatic symptom monitoring (ASM) with optimized analgesic care management by a nurse-physician team. Data from participants in the telecare intervention arm (n = 124) of a randomized control trial of SCOPE were analysed to determine the acceptability of the telecare intervention as indicated by patient use and satisfaction. Results Most (93.5%) patients completed at least one ASM report, selecting equally web-based (49%) or interactive voice-recorded (51%) reporting. The median number of ASM reports and nurse contacts per patient was 15 and 12, respectively. Of 12 demographic and clinical factors examined, none predicted the number of ASM reports, whereas nurse contacts were more frequent in patients with higher pain severity or receiving opioids. Only a minority of ASM reports required an expedited nurse call, with the most frequent alerts being for a medication change, a nurse call or side effects. Most (92%) patients rated ASM as easy to use and found the ASM reporting (76%) and nurse contacts (81%) very or moderately helpful. Nearly three-fourths of patients rated their overall pain treatment as good to excellent. The most common suggestions from patient feedback were for a free-text messaging function, more frequent nurse contact and less redundancy in ASM reporting items. Discussion Participants generally found the telecare intervention a user-friendly and helpful approach for treating persistent musculoskeletal pain.

The constitutive activation of signal transducer and activator of transcription 3 (STAT3) is frequently detected in most types of human cancer where it plays important roles in survival, drug resistance, angiogenesis, and other functions. Targeting constitutive STAT3 signaling is thus an attractive therapeutic approach for these cancers. We have recently developed novel small-molecule STAT3 inhibitors, known as FLLL31 and FLLL32, which are derived from curcumin (the primary bioactive compound of turmeric). These compounds are designed to bind selectively to Janus kinase 2 and the STAT3 Src homology-2 domain, which serve crucial roles in STAT3 dimerization and signal transduction. Here we show that FLLL31 and FLLL32 are effective inhibitors of STAT3 phosphorylation, DNA-binding activity, and transactivation in vitro, leading to the impediment of multiple oncogenic processes and the induction of apoptosis in pancreatic and breast cancer cell lines. FLLL31 and FLLL32 also inhibit colony formation in soft agar and cell invasion and exhibit synergy with the anticancer drug doxorubicin against breast cancer cells. In addition, we show that FLLL32 can inhibit the induction of STAT3 phosphorylation by IFNα and interleukin-6 in breast cancer cells. We also show that administration of FLLL32 can inhibit tumor growth and vascularity in chicken embryo xenografts as well as substantially reduce tumor volumes in mouse xenografts. Our findings highlight the potential of these new compounds and their efficacy in targeting pancreatic and breast cancers that exhibit constitutive STAT3 signaling. Cancer Res; 70(6); 2445–54

Constitutive activation of signal transducer and activator of transcription 3 (STAT3) signaling is frequently detected in cancer, promoting its emergence as a promising target for cancer treatment. Inhibiting constitutive STAT3 signaling represents a potential therapeutic approach. We used structure-based design to develop a nonpeptide, cell-permeable, small molecule, termed as LLL12, which targets STAT3. LLL12 was found to inhibit STAT3 phosphorylation (tyrosine 705) and induce apoptosis as indicated by the increases of cleaved caspase-3 and poly (ADP-ribose) polymerase in various breast, pancreatic, and glioblastoma cancer cell lines expressing elevated levels of STAT3 phosphorylation. LLL12 could also inhibit STAT3 phosphorylation induced by interleukin-6 in MDA-MB-453 breast cancer cells. The inhibition of STAT3 by LLL12 was confirmed by the inhibition of STAT3 DNA binding activity and STAT3-dependent transcriptional luciferase activity. Downstream targets of STAT3, cyclin D1, Bcl-2, and survivin were also downregulated by LLL12 at both protein and messenger RNA levels. LLL12 is a potent inhibitor of cell viability, with half-maximal inhibitory concentrations values ranging between 0.16 and 3.09 µM, which are lower than the reported JAK2 inhibitor WP1066 and STAT3 inhibitor S3I-201 in six cancer cell lines expressing elevated levels of STAT3 phosphorylation. In addition, LLL12 inhibits colony formation and cell migration and works synergistically with doxorubicin and gemcitabine. Furthermore, LLL12 demonstrated a potent inhibitory activity on breast and glioblastoma tumor growth in a mouse xenograft model. Our results indicate that LLL12 may be a potential therapeutic agent for human cancer cells expressing constitutive STAT3 signaling.

Curcumin, the active component of turmeric, has been shown to protect against carcinogenesis and prevent tumor development in cancer. To enhance its potency, we tested the efficacy of synthetic curcumin analogues, known as FLLL11 and FLLL12, in cancer cells. We examined the impact of FLLL11 and FLLL12 on cell viability in eight different breast and prostate cancer cell lines. FLLL11 and FLLL12 (IC(50) values 0.3-5.7 and 0.3-3.8 micromol/L, respectively) were substantially more potent than curcumin (IC(50) values between 14.4-50 micromol/L). FLLL11 and FLLL12 were also found to inhibit AKT phosphorylation and downregulate the expression of HER2/neu. In addition, we demonstrate for the first time that FLLL11 and FLLL12 inhibit phosphorylation of signal transducer and activator of transcription (STAT) 3, an oncogene frequently found to be persistently active in many cancer types. The inhibition of STAT3 signaling was confirmed by the inhibition of STAT3 DNA binding and STAT3 transcriptional activity. Furthermore, FLLL11 and FLLL12 were more effective than curcumin in inhibiting cell migration and colony formation in soft agar as well as inducing apoptosis in cancer cells. These results indicate that FLLL11 and FLLL12 exhibit more potent activities than curcumin on the inhibition of STAT3, AKT, and HER-2/neu, as well as inhibit cancer cell growth and migration, and may thus have translational potential as chemopreventive or therapeutic agents for breast and prostate cancers.

Background Targeting Signal Transducer and Activator of Transcription 3 (STAT3) signaling is an attractive therapeutic approach for most types of human cancers with constitutively activated STAT3. A novel small molecular STAT3 inhibitor, FLLL32 was specifically designed from dietary agent, curcumin to inhibit constitutive STAT3 signaling in multiple myeloma, glioblastoma, liver cancer, and colorectal cancer cells. Results FLLL32 was found to be a potent inhibitor of STAT3 phosphorylation, STAT3 DNA binding activity, and the expression of STAT3 downstream target genes in vitro, leading to the inhibition of cell proliferation as well as the induction of Caspase-3 and PARP cleavages in human multiple myeloma, glioblastoma, liver cancer, and colorectal cancer cell lines. However, FLLL32 exhibited little inhibition on some tyrosine kinases containing SH2 or both SH2 and SH3 domains, and other protein and lipid kinases using a kinase profile assay. FLLL32 was also more potent than four previously reported JAK2 and STAT3 inhibitors as well as curcumin to inhibit cell viability in these cancer cells. Furthermore, FLLL32 selectively inhibited the induction of STAT3 phosphorylation by Interleukin-6 but not STAT1 phosphorylation by IFN-γ. Conclusion Our findings indicate that FLLL32 exhibits potent inhibitory activity to STAT3 and has potential for targeting multiple myeloma, glioblastoma, liver cancer, and colorectal cancer cells expressing constitutive STAT3 signaling.