Approximately 28 million people in the United States have precancerous colonic adenomas with many at high risk of developing colorectal cancer who could benefit from a pharmacological approach to prevent malignant progression. Clinical, epidemiological, and preclinical studies have reported or provided mechanistic evidence that nonsteroidal anti-inflammatory drugs (NSAIDs) can reduce adenoma formation and the risk of developing colorectal cancer. Unfortunately, the long-term use of NSAIDs is not recommended because of potentially fatal toxicities resulting from cyclooxygenase (COX) inhibition and the depletion of physiologically important prostaglandins. However, multiple investigators have concluded that the mechanism responsible for the antineoplastic activity of NSAIDs does not require COX inhibition, which suggests the feasibility of developing safer and more efficacious derivatives for the treatment or prevention of colorectal cancer by targeting such mechanisms. We have widely reported that the NSAID, sulindac, inhibits certain phosphodiesterase (PDE) isozymes to increase intracellular cyclic guanosine monophosphate (cGMP) levels and activate protein kinase G (PKG) at concentrations that inhibit cancer cell growth in vitro. PDE5 and PDE10 are potential targets given that both are overexpressed in colon adenomas and adenocarcinomas and essential for colon cancer cell proliferation. An extensive medicinal chemistry campaign was conducted to identify novel sulindac derivatives lacking COX inhibitory activity with increased potency and selectivity to inhibit cancer cell growth. From a large collection of over 1500 compounds sharing the indene scaffold of sulindac, a series of derivatives were identified that inhibit cancer cell growth with high potency and selectivity by a mechanism involving the activation of cGMP/PKG signaling. Development candidates have been identified that block the oncogenic effects from APC gene mutations responsible for most human colorectal cancers by suppressing β-catenin-dependent transcriptional activity. This review describes the scientific rationale for the development of sulindac derivatives lacking COX inhibitory activity with improved potency and selectivity to inhibit PDE5 and/or PDE10 for the treatment or prevention of colorectal cancer.
To study on the adequacy of ultrasound guided FNACs in abdominal lesions and to evaluate and compare the adequate samples for malignant versus benign lesions and primary versus metastatic lesions in abdominal FNACs. This retrospective study included 854 cases of abdominal ultrasound guided fine needle aspiration cytology (FNAC) performed from January 2007 to Dec 2016. 22–23 G needle with disposable 10 cc syringes were used. Patients with severe coagulopathy were excluded from the procedure. Aspirated material were reported by experienced cytopathologists. The mean age was 39.5 years, with M:F of 1.25:1. The sample adequacy in male is 77.68% and female is 72.56%. The overall sample adequacy was 644 out of 854 (75.4%), which however ranges from 60% to 100% according to decades. The commonest site aspirated were lymph nodes (415/854 = 48.59%) followed by liver (274/854 = 32.08%). There is highly dependent relationship between adequacy of sample and patients age (Pearson chi square value - 58.594, Significance 8.78758E-10). High degree of positive correlation (correlation 0.906935) also noted between cytological adequacy and patients age. There is also high degree of positive correlation between malignancy and age of the patient (correlation −0.895332). Ultrasound guided fine needle aspiration cytology is very versatile, simple, economical and safe technique with potential high diagnostic yield.
A recent work by Nishina et al. provides new evidence that DPP4 inhibitors exert antitumor effects against hepatocellular carcinoma (HCC) by orchestrating immune responses.
We focused on defining the role of the E3 ligase NEDD4 in NSCLC cell afatinib resistance. Afatinib resistant H1975 clones over-expressed NEDD4 and c-MET compared to control clones and expressed less ERBB1, ERBB3, ERBB4 and PTEN than control clones. Knock down of NEDD4 enhanced the expression of PTEN, ERBB1/3/4 and c-MET. This was also associated with a ∼3-fold enhancement in both mTOR expression and mTOR phosphorylation and a ∼4-fold elevation in phospho-ULK-1 S757 levels. In the absence of NEDD4 or the autophagy regulatory protein Beclin1, neither the drug combination of [pemetrexed + sildenafil] nor the HDAC inhibitor sodium valproate was as capable of: reducing the expression of ERBB1/3/4; reducing phosphorylation of ULK-1 S757; or at enhancing the phosphorylation of ULK-1 S317 and ATG13 S318. [Pemetrexed + sildenafil] exposure, via autophagic degradation, reduced the expression of multiple HDACs. Reduced expression of Class I HDACs lowered the expression of ERBB1/3/4 and PTEN. Treatment of afatinib resistant clones lacking NEDD4 with [pemetrexed + sildenafil] or sodium valproate resulted in a weaker induction of autophagosome and autolysosome formation and with reduced cell killing. Knock down of NEDD4 reduced [pemetrexed + sildenafil] lethality; knock down of PTEN enhanced drug-induced killing. Combined knock down of NEDD4 and PTEN reduced the elevated amount of killing caused by PTEN knock down alone back to basal levels. Collectively, our data argue that NEDD4 plays an essential role in maintaining the afatinib-resistant phenotype in our resistant H1975 clones.
In this brief commentary, we discuss oral novel agents within in the armementarium of therapeutic options for Canadian patients with chronic lymphocytic leukemia (CLL). Previously limited to chemotherapy, the Canadian patient with relapsed or refractory CLL has the option of treatment with B-cell receptor inhibitors ibrutinib or idelalisib (combined with rituximab), both individually showing superiority to anti-CD20 monoclonal antibody comparators regardless of high-risk deletion 17p (del(17p)) status in phase 3 clinical trials. BCL2-inhibitor venetoclax shows impressive efficacy for previously-treated patients with del(17p), but though approved, it is not yet funded. For treatment-naïve patients, ibrutinib has proven superior to chemotherapy for those over 65 with comorbidities, but its role remains to be seen for the young and/or fit. Whereas oral novel agents are generally well-tolerated, some side effects, such as infection, hemorrhage, cardiac arrhythmias and tumour lysis syndrome, can be severe, therefore expert clinical vigilance is essential. Regarding sequencing of these agents, most patients failing ibrutinib or idelalisib do respond to venetoclax. While future studies using combinations of novel agents may eventually obviate the use of chemotherapy for CLL, regimens that can be stopped when minimal residual disease is achieved, such as venetoclax, are particularly relevant for our publicly-funded health care system. For Canadian CLL patients, the availability of oral novel agents has greatly expanded treatment options and is improving outcomes.
