Colorectal cancer (CRC) is the second-leading cause of cancer-related mortality in the United States. Over 50% of patients with CRC will develop local recurrence or distant organ metastasis. Cancer stem cells play a major role in the survival and metastasis of cancer cells. In this study, we examined the effects of novel AMP-activated protein kinase (AMPK) activating compounds on CRC metastatic and stem cell lines as potential candidates for chemotherapy. We found that activation of AMPK by all fluorinated N,N-diarylureas (FND) compounds at micromolar levels significantly inhibited the cell cycle progression and subsequent cellular proliferation. Additionally, we demonstrated that select FNDs significantly increased apoptosis in CRC metastatic and cancer stem cells. Therefore, FNDs hold considerable promise in the treatment of metastatic CRC, through elimination of both regular cancer cells and cancer stem cells.
C oronary artery air embolism is a rare complication in the non-operating room anesthesia environment. In this setting, coronary artery air embolism is generally caused by communication between the atmosphere and the pulmonary venous system or by the creation of a bronchialvenous or alveolar-venous fistula during lung biopsy. 1 Typical presentation is a result of the ensuing myocardial ischemia, and includes chest pain, arrhythmia, ST segment changes, bradycardia, hypotension, and cardiovascular collapse. 2 Figure 1 represents the intraprocedural computed tomography imaging of a 74-yr-old woman who underwent percutaneous lung biopsy. Clearly visible is the airfluid level in the ascending aorta, just distal to the right coronary artery ostia. Figure 2 shows air in the proximal right coronary artery. This patient's procedural course was complicated by profound bradycardia, arrhythmia, and cardiogenic shock secondary to acute myocardial ischemia.Risk of coronary artery air embolism is underappreciated outside the cardiac operating room; thus, the anesthesiologist must maintain a high degree of suspicion and closely monitor the electrocardiogram for change. Risk factors include coughing, positive pressure ventilation, biopsy of cavitary lesions, and use of needle-within-needle biopsy systems. 3 In supine patients, the right ventricle is particularly vulnerable to coronary artery air embolism secondary to the anterior takeoff of the right coronary. Treatment involves immediate Trendelenburg positioning to prevent cerebral air embolism, an inspiratory oxygen fraction of 1.0, central access, and catecholamine support of cardiac function and coronary perfusion pressure. Transcutaneous or transvenous pacing, as well as coronary angiography, aspiration, and localized vasodilator injection have also been trialed successfully in the catheterization laboratory. 3 Finally, extracorporeal membrane oxygenation or cardiac bypass may be indicated if other measures fail.
Colorectal (CRC) cancer is the second leading cause of cancer deaths in the US; treatment of metastatic CRCs is limited due to drug resistance and eventual relapse. Cancer stem cells and PI3K mutation (i.e., pik3ca mutation) have been implicated in the relapse and lack of treatment response for many cancers including CRCs; therefore, it is critical to develop a therapeutic strategy that eliminates both the fast-growing cancer cells and the more resistant cancer stem cells. The purpose of the present study was to evaluate the anticancer activity of recently-described, novel AMPK activators, fluorinated N, N-diarylureas (FNDs), against CRC metastatic cell lines, pik3ca mutant cell lines, and CRC stem cells. METHODS. i) First, to assess AMPK activation, metastatic CRC cell lines (HT29 and KM20 cells), HCT116 pik3ca wild-type (WT) and mutant (MUT) cell lines, and CRC stem cell lines (from Celprogen) were treated with varying concentrations of 8 FNDs (4a, 4b, 4h, 4j, 4k, 4z, 4aa, 4bb). AMPK activation and activation of the upstream regulator, LKB1, was assessed by western blot. ii) Next, we determined the effect of the FNDs and, for comparison, metformin (an AMPK activator) on induction of cell cycle suppression and induction of apoptosis as assessed by cyclin D1 expression and PARP cleavage, respectively; β-actin antibody was used as a loading control. RESULTS. i) Treatment with the FNDs resulted in AMPK activation in HT29 and KM20 cells and CRC stem cells at concentrations as low as 10 μM with a peak activation at 12 h. We observed LKB1-independent AMPK kinase activation. Decreased LKB1 phosphorylation after FND treatment was dose dependent (i.e., decreased by ∼50% at 10 μM and undetectable at 50 μM). ii) All 8 FNDs (at a 25 μM dosage) completely suppressed cyclin D1 expression in HT29 and KM20 cells; a similar cyclin D1 suppression was noted with metformin at a 500x higher dosage (i.e., 10mM). Five of the 8 FNDs (4b, 4j, 4z, 4aa, 4bb) increased PARP cleavage in HT29 and KM20 cells. We used these 5 FNDs (at a dosage of 50 μM each) to treat the CRC stem cell lines; cyclin D1 suppression was noted for all 5 FNDs but strong induction of apoptosis was only identified using the 4b FND. Finally, we treated HCT116 pik3ca WT and MUT cell lines with 4b FND and found that cyclin D1 expression was completely suppressed at 40 μM and induction of apoptosis was noted at a dosage of 20 μM. CONCLUSIONS. We demonstrate cell cycle suppression and apoptosis in CRC cells and stem cells using the recently-developed FND compounds with the 4b compound as the most effective. These compounds appear to have considerable promise as a targeted cancer stem cell-specific agents and offer a potentially novel strategy for the treatment of CRC metastases. Citation Format: Piotr Rychahou, Dasha Kenlan, Vitaliy M. Sviripa, David S. Watt, B. Mark Evers. Fluorinated N, N-diarylureas treatment as effective strategy to target colorectal cancer stem cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1222.
W e would like to thank Hess and Long 1 for their comments on our article, 2 who emphasized the role of acidemia-associated coagulopathy in terms of decreasing fibrinogen concentration, reducing coagulation factors and promoting a state of hypocoagulability. Furthermore, the correction of the state of acidemia with bicarbonate infusion does not correct or alleviate coagulopathy, suggesting that, in the presence of hemorrhagic shock, it is mandatory to avoid or decrease the severity of acidemia and hypothermia to improve outcome. [3][4][5]
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