Conjugated docosahexaenoic acid suppresses KPL-1 human breast cancer cell growth in vitro and in vivo: potential mechanisms of action

Introduction The present study was conducted to examine the effect of conjugated docosahexaenoic acid (CDHA) on cell growth, cell cycle progression, mode of cell death, and expression of cell cycle regulatory and/or apoptosis-related proteins in KPL-1 human breast cancer cell line. This effect of CDHA was compared with that of docosahexaenoic acid (DHA). Methods KPL-1 cell growth was assessed by colorimetric 3- (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay; cell cycle progression and mode of cell death were examined by flow cytometry; and levels of expression of p53, p21Cip1/Waf1, cyclin D1, Bax, and Bcl-2 proteins were examined by Western blotting analysis. In vivo tumor growth was examined by injecting KPL-1 cells subcutaneously into the area of the right thoracic mammary fat pad of female athymic mice fed a CDHA diet. Results CDHA inhibited KPL-1 cells more effectively than did DHA (50% inhibitory concentration for 72 hours: 97 μmol/l and 270 μmol/l, respectively). With both CDHA and DHA growth inhibition was due to apoptosis, as indicated by the appearance of a sub-G1 fraction. The apoptosis cascade involved downregulation of Bcl-2 protein; Bax expression was unchanged. Cell cycle progression was due to G0/G1 arrest, which involved increased expression of p53 and p21Cip1/Waf1, and decreased expression of cyclin D1. CDHA modulated cell cycle regulatory proteins and apoptosis-related proteins in a manner similar to that of parent DHA. In the athymic mouse system 1.0% dietary CDHA, but not 0.2%, significantly suppressed growth of KPL-1 tumor cells; CDHA tended to decrease regional lymph node metastasis in a dose dependent manner. Conclusion CDHA inhibited growth of KPL-1 human breast cancer cells in vitro more effectively than did DHA. The mechanisms of action involved modulation of apoptosis cascade and cell cycle progression. Dietary CDHA at 1.0% suppressed KPL-1 cell growth in the athymic mouse system.</p

Cerebral hypoperfusion accelerates cerebral amyloid angiopathy and promotes cortical microinfarcts

Cortical microinfarcts (CMIs) observed in brains of patients with Alzheimer’s disease tend to be located close to vessels afflicted with cerebral amyloid angiopathy (CAA). CMIs in Alzheimer’s disease are preferentially distributed in the arterial borderzone, an area most vulnerable to hypoperfusion. However, the causal association between CAA and CMIs remains to be elucidated. This study consists of two parts: (1) an observational study using postmortem human brains (n = 31) to determine the association between CAA and CMIs, and (2) an experimental study to determine whether hypoperfusion worsens CAA and induces CMIs in a CAA mouse model. In postmortem human brains, the density of CMIs was 0.113/cm2 in mild, 0.584/cm2 in moderate, and 4.370/cm2 in severe CAA groups with a positive linear correlation (r = 0.6736, p < 0.0001). Multivariate analysis revealed that, among seven variables (age, disease, senile plaques, neurofibrillary tangles, CAA, atherosclerosis and white matter damage), only the severity of CAA was a significant multivariate predictor of CMIs (p = 0.0022). Consistent with the data from human brains, CAA model mice following chronic cerebral hypoperfusion due to bilateral common carotid artery stenosis induced with 0.18-mm diameter microcoils showed accelerated deposition of leptomeningeal amyloid β (Aβ) with a subset of them developing microinfarcts. In contrast, the CAA mice without hypoperfusion exhibited very few leptomeningeal Aβ depositions and no microinfarcts by 32 weeks of age. Following 12 weeks of hypoperfusion, cerebral blood flow decreased by 26% in CAA mice and by 15% in wild-type mice, suggesting impaired microvascular function due to perivascular Aβ accumulation after hypoperfusion. Our results suggest that cerebral hypoperfusion accelerates CAA, and thus promotes CMIs

Conjugated docosahexaenoic acid suppresses KPL-1 human breast cancer cell growth in vitro and in vivo: potential mechanisms of action Conjugated docosahexaenoic acid suppresses KPL-1 human breast cancer cell growth in vitro and in vivo: potential mechanis

Abstract Introduction The present study was conducted to examine the effect of conjugated docosahexaenoic acid (CDHA) on cell growth, cell cycle progression, mode of cell death, and expression of cell cycle regulatory and/or apoptosis-related proteins in KPL-1 human breast cancer cell line. This effect of CDHA was compared with that of docosahexaenoic acid (DHA)

A Case Report of Surgical Resections with Local and Systemic Chemotherapy for Three Recurrences of Colon Cancer Occurring Ten Years after Colectomy

A 56-year-old Japanese woman who underwent a curative resection of ascending colon cancer at 43 years of age was found to have a tumor in her lower left abdominal cavity by computed tomography at 53 years of age. The tumor in the omentum was resected and identified as an adenocarcinoma compatible with metastasis from the primary ascending colon cancer. Although the patient received adjuvant chemotherapy with tegafur uracil and calcium folinate, liver metastasis was detected 9 months after the first recurrence. A segmentectomy and hepatectomy was performed, and histopathological findings indicated metastasis from the primary colon cancer. A third recurrence was detected in the right abdominal cavity 7 months after the second surgery. The patient received 5 cycles of combination chemotherapy consisting of folinic acid, fluorouracil and irinotecan before the third operation. The metastatic tumor resection together with intraperitoneal chemotherapy was performed, and histopathological findings indicated metastasis from the primary colon cancer. After the third surgery, the patient received adjuvant chemotherapy consisting of 5 cycles of folinic acid, fluorouracil and oxaliplatin. The patient is well with no evidence of recurrence 12 months after the third recurrence. This case suggests that colon cancer can be dormant for over 10 years and that long-term follow-up is required after curative resection. Aggressive local as well as systemic chemotherapy may be required for the management of colon cancer recurrence

The First Autopsy Case of Fatal Acute Cardiac Failure after Administration of Carfilzomib in a Patient with Multiple Myeloma

Carfilzomib (CFZ) improves progression-free survival for patients with relapsed or refractory multiple myeloma (MM) but has shown higher frequency of cardiovascular adverse events (CVAEs) than other proteasome inhibitors. We report the first autopsy case of acute death from cardiac failure shortly after administration of carfilzomib. A 74-year-old female was diagnosed with IgA MM after a 2-year period of smoldering MM. She was refractory to both bortezomib plus dexamethasone and lenalidomide plus dexamethasone therapies, so she subsequently received CFZ in combination with lenalidomide and dexamethasone. The day after the start of the therapy, she complained of severe dyspnea with a significant decline in left ventricular ejection fraction. Her acute cardiac failure rapidly progressed, and she died on day 7 of the start of CFZ. The autopsy showed invasion of inflammatory cells between the myocardial cells and very little myocardial necrosis. There was no obvious thrombus in the coronary artery of the heart, and no infarction or amyloid deposition was observed in the myocardium. Pathological findings of hypersensitivity myocarditis, a drug-induced cardiomyopathy, appeared to agree with this case except for absence of an eosinophilic infiltration of the myocardium. A CFZ-induced CVAE is generally considered reversible. However, rapidly progressing fatal heart failure like in our case is rare. To characterize CFZ-associated CVAE, further case collection is needed