Phosphosulindac (OXT-328) Selectively Targets Breast Cancer Stem Cells In Vitro and in Human Breast Cancer Xenografts

Pharmacological targeting of breast cancer stem cells (CSCs) is highly promising for the treatment of breast cancer, as the small population of CSCs appears responsible for tumor initiation and progression and also for resistance to conventional treatment. Here we report that the novel phosphosulindac (OXT-328, PS) selectively and effectively eliminates breast CSCs both in vitro and in vivo. PS reduced cell proliferation and induced apoptosis in various breast CSCs. Breast CSCs are resistant to conventional cancer drugs but are sensitive to PS. Long-term treatment of mixtures of cultured breast CSCs and breast cancer cells with PS preferentially eliminated the CSCs. PS impaired the ability of CSCs to form mammospheres and markedly suppressed the expression of CSC-related genes. More importantly, PS prevented by half (p =.06) the formation of tumors initiated by CSCs in immunodeficient mice, and inhibited by 83% (p <.05) the growth of already formed breast cancer xenografts, reducing the proportion of CSCs in them. PS suppressed the Wnt/β-catenin pathway by stimulating the degradation of β-catenin and its relocalization to the cell membrane and also blocked the epithelial-mesenchymal transition and the generation of breast CSCs. These results indicate that PS has a strong inhibitory effect against breast cancer, acting, at least in part, by targeting CSCs through a signaling mechanism involving Wnt signaling. STEM Cells2012;30:2065-2075.     

Circadian periodicity and other clinical features of biliary pain.

We studied the time of onset and other clinical features of biliary pain in 54 patients living in Northern Italy. All patients had cholelithiasis documented by ultrasonography. The time of onset of pain followed a circadian periodicity with its peak occurring at 9:30 p.m. The typical biliary pain was steady, mostly localized in the right upper quadrant of the abdomen or the epigastrium, lasted over 1 h, and required analgesics for relief. The pain was not related to meals or body position. What precipitates biliary pain is still an enigma.     

Sulindac sulfide, an aspirin-like compound, inhibits proliferation, causes cell cycle quiescence, and induces apoptosis in HT-29 colon adenocarcinoma cells.

Nonsteroidal antiinflammatory drugs (NSAIDs), have cancer preventive and tumor regressive effects in the human colon. They lower the incidence of and mortality from colorectal cancer and sulindac reduces the number and size of polyps in patients with familial adenomatous polyposis. We studied the effect of sulindac, and its metabolite sulindac sulfide, on the proliferation of HT-29 colon adenocarcinoma cells. Both compounds reduced the proliferation rate of these cells, changed their morphology, and caused them to accumulate in the G0/G1 phase of the cell cycle. These responses were time- and concentration-dependent and reversible. In addition, these compounds reduced the level and activity of several cyclin-dependent kinases (cdks), which regulate cell cycle progression. Sulindac and sulindac sulfide also induced apoptosis in these cells at concentrations that affected their proliferation, morphology, and cell cycle phase distribution. Sulindac sulfide was approximately sixfold more potent than sulindac in inducing these cellular responses. Our results indicate that inhibition of cell cycle progression and induction of apoptotic cell death contribute to the anti-proliferative effects of sulindac and sulindac sulfide in HT-29 cells. These findings may be relevant to the cancer preventive and tumor regressive effects of these compounds in humans.     

Loss of colonic HLA antigens in familial adenomatous polyposis.

The loss of HLA antigens by neoplastic cells is considered important for tumor growth and metastasis, since it may allow tumors to escape immune surveillance. We studied the expression of HLA class I and II antigens in the colons of 10 patients with familial adenomatous polyposis (FAP), a condition which leads inevitably to colorectal cancer. Expression of HLA class antigens was studied by immunohistochemistry in (a) adenomas from patients with FAP, (b) histologically normal mucosa distant from the adenomas, and (c) histologically normal colonic mucosa from normal subjects. The expression of HLA class I and II antigens was decreased in histologically normal mucosa from FAP patients compared to normal controls. Adenomas showed a similar but quantitatively more pronounced reduction (or loss) of HLA antigen expression. The reduction of HLA expression in adenomas was comparable to that observed in sporadic colon carcinomas. This generalized suppression of HLA gene expression in the colon of FAP patients, which precedes the onset of overt histological manifestations of neoplasia, may be an important early event in colon carcinogenesis.     

Neuropsychological assessment of cognitive function in chronic alcohol-dependent patients and patients with Alzheimer's disease

BACKGROUND: Heavy and chronic alcohol dependence and Alzheimer's disease may share some neuropsychological characteristics. PATIENTS AND METHODS: The pattern of neuropsychological characteristics of 33 alcohol-dependent patients who reported memory disturbances were evaluated and compared to the neuropsychological performance of 38 patients with mild-stage Alzheimer's disease and 73 healthy subjects, serving as controls. Alcohol-dependent patients were examined with tools concerning the pattern of alcohol abuse and problems related to alcohol consumption. All groups completed a full battery of neuropsychological tests for the assessment of cognitive functions, such as different kinds of memory, attention, executive function etc. RESULTS: Alcohol-dependent patients fared worse compared to the control subjects in every test used. The comparison of alcohol-dependent patients versus patients with Alzheimer's disease showed that the latter are much more burdened, as far as cognition is concerned, in all aspects of memory. CONCLUSION: Alcohol-dependent patients, even if they are not demented, have mild cognitive impairment in all domains of cognition (memory and frontal functions) in comparison with controls which performed within the norms. Verbal fluency, working memory and frontal functions were impaired at the same degree in alcohol-dependent patients and in patients with Alzheimer's disease. Memory problems were more pronounced in Alzheimer's disease patients.     

Expression of apoptosis-related proteins and response to chemoradiotherapy and prognosis in esophageal cancer

Purpose

Defects in the apoptotic pathway confer insensitiviry to the cytotoxic effects of chemotherapy and hence represent an important distal mechanism for the development of chemoresistance. In this study, we sought to obtain results on which to base clinical hypotheses about this mechanism. The aim of this study was to analyze the correlation of the expression of three of these apoptotic molecules, Bc1-2, Bax and Bc1-X, with chemoradiotherapy response and clinical outcome in patients with esophageal tumors.

Patients and methods

Tumor biopsy specimens from 42 patients were assessed by immunohistochemistry for expression of Bc1-2, Bax and Bc1-X proteins. The expression of these proteins was correlated with response to chemoradiotherapy in 24 patients.

Results

The overall expression of Bc1-2, Bax and Bc1-X was 29%, 68% and 88%, respectively. Bax expression was lower in lymph-node-positive tumors (p = 0.01). Probability of response to chemoradiotherapy was higher in Bax-negative tumors than in Bax-positive tumors (80% vs 35%, p = 0.1). In addition, 62% of patients with low Bc1-X expression (< 50% stained cells) showed response to chemoradiotherapy, as opposed to only 33% of patients with higher Bc1-X expression (p = 0.2). Patients with low Bc1-X expression showed a significantly better prognosis than those with high Bc1-X expression (p =0.02), and a tendency towards higher survival was detected in Bc1-2 positive patients.

Conclusion

The correlation detected between Bax and Bc1-X expression and response to chemoradiotherapy suggests that screening for these apoptosisrelated proteins could be useful in determining patients who would benefit from chemoradiotherapy. However, further investigation is warranted to elucidate the potential role of Bax in taxane-treated patients. Clearly, since high Bc1-X expression conferred poor survival in our study, it could be a useful prognostic marker in esophageal cancer.     

NO-releasing NSAIDs and colon cancer chemoprevention: a promising novel approach (Review)

The chemoprevention of colon cancer, the second leading cause of cancer-related deaths in the United States, has been pursued actively during the last two decades. Methodological problems and those stemming from the available agents per se have constrained this difficult task; to some extent, these problems persist to date. That NSAIDs decrease the incidence of and mortality from colon cancer has been a major advance in chemoprevention. These compounds are, however, limited by their significant side effects. NO-releasing NSAIDs (NO-NSAIDs) are a novel class of compounds, synthesized to overcome the limitations of NSAIDs. In general, they appear safer and much more effective than their traditional counterparts. We review their structural features, metabolism and pharmacological actions. In vitro and in vivo studies indicate that they are much more effective than traditional NSAIDs in modulating colonocyte kinetics and the formation of premalignant colon lesions. Their mechanism of action is complex and not fully understood, including modulation of NO synthesis, signaling mediated via NF-kappaB and likely other pathways. Current early findings indicate that NO-NSAIDs may play a highly promising role in the chemoprevention of colon cancer.     

Nitric oxide-releasing nonsteroidal anti-inflammatory drugs (NSAIDs) alter the kinetics of human colon cancer cell lines more effectively than traditional NSAIDs: implications for colon cancer chemoprevention

Nitric oxide-releasing nonsteroidal anti-inflammatory drugs (NO-NSAIDs), consisting of a known nonsteroidal anti-inflammatory drug (NSAID) and a nitric oxide (NO)-releasing group, are reported safer than NSAIDS: To assess their potential in colon cancer chemoprevention, we studied in vitro the effect of NO-aspirin, NO-sulindac, and NO-ibuprofen on colonocyte kinetics. These three NO-NSAIDs reduced the growth of cultured HT-29 colon adenocarcinoma cells much more effectively than the corresponding NSAIDs; e.g., at 24 h, their IC(50) values were as follows: (a) aspirin, >5000 microM; (b) NO-aspirin, 1 microM; (c) sulindac, 750 microM; (d) NO-sulindac, 150 microM; (e) ibuprofen, >1000 microM; and (f) NO-ibuprofen, 42 microM. This effect was due to inhibition of proliferation and induction of apoptosis and perhaps to the induction of novel cell changes, characterized by extensive DNA degradation. NO-NSAIDs also blocked the G(0)-G(1) to S cell cycle transition. Their superior effectiveness compared with traditional NSAIDs, combined with their reported safety, makes them promising candidates for chemopreventive agents against colon cancer.