Activation of CD44, a receptor for extracellular matrix components, protects chronic lymphocytic leukemia cells from spontaneous and drug induced apoptosis through MCL-1.

Survival of chronic lymphocytic leukemia (CLL) cells in vivo is supported by the tissue microenvironment, which includes components of the extracellular matrix. Interactions between tumor cells and the extracellular matrix are in part mediated by CD44, whose principal ligand is hyaluronic acid. Here, we show that CD44 is more highly expressed on CLL cells of the clinically more progressive immunglobulin heavy chain variable gene (IGHV)-unmutated subtype than on cells of the IGHV-mutated type. Engagement of CD44 activated the phosphatidylinositol 3-kinase (PI3K)/AKT and mitogen activated protein kinase (MAPK)/ERK pathways and increased myeloid cell leukemia sequence 1 (MCL-1) protein expression. Consistent with the induction of these anti-apoptotic mechanisms, CD44 protected CLL cells from spontaneous and fludarabine-induced apoptosis. Obatoclax, an antagonist of MCL-1, blocked the pro-survival effect of CD44. In addition, obatoclax synergized with fludarabine to induce apoptosis of CLL cells. In conclusion, components of the extracellular matrix may provide survival signals to CLL cells through engagement of CD44. Inhibition of MCL-1 is a promising strategy to reduce the anti-apoptotic effect of the microenvironment on CLL cells.

Pioglitazone attenuates acute cocaine toxicity in rat isolated heart: potential protection by metabolic modulation.

BACKGROUND: The authors tested whether cocaine depresses mitochondrial acylcarnitine exchange and if a drug that enhances glucose metabolism could protect against cocaine-induced cardiac dysfunction. METHODS: Oxygen consumption with and without cocaine was compared in rat cardiac mitochondria using octanoylcarnitine (lipid) or pyruvate (nonlipid) substrates. Isolated hearts from rats with or without a pioglitazone-supplemented diet were exposed to cocaine. RESULTS: The 0.5 mM cocaine inhibited respiration supported by octanoylcarnitine (82 ± 10.4 and 45.7 ± 4.24 ngatomO min⁻¹ · mg⁻¹ · protein ± SEM, for control and cocaine treatment, respectively; P < 0.02) but not pyruvate-supported respiration (281 ± 12.5 and 267 ± 12.7 ngatomO min⁻¹ · mg⁻¹ · protein ± SEM; P = 0.45). Cocaine altered contractility, lusitropy, coronary resistance, and lactate production in isolated heart. These effects were each blunted in pioglitazone-treated hearts. The pioglitazone diet attenuated the drop in the rate-pressure product (P = 0.002), cocaine-induced diastolic dysfunction (P = 0.04), and myocardial vascular resistance (P = 0.05) compared with that of controls. Lactate production was higher in pretreated hearts (P = 0.008) and in ventricular myocytes cultured with pioglitazone (P = 0.0001). CONCLUSIONS: Cocaine inhibited octanoylcarnitine-supported mitochondrial respiration. A pioglitazone diet significantly attenuated the effects of cocaine on isolated heart. The authors postulate that inhibition of acylcarnitine exchange could contribute to cocaine-induced cardiac dysfunction and that metabolic modulation warrants additional study.

Local anesthetic toxicity and lipid resuscitation in pregnancy.

PURPOSE OF REVIEW: Lipid emulsion has emerged as an effective treatment of local anesthetic-induced cardiac arrest, but its therapeutic application for the obstetric patient requires definition at present. This review discusses clinical reports, relevant laboratory studies, and future directions for the development of an optimal protocol for lipid resuscitation in pregnancy. RECENT FINDINGS: Several mechanisms have been postulated to account for the apparent enhanced sensitivity to local anesthetic systemic toxicity during pregnancy. One case report of lipid resuscitation in the pregnant patient demonstrates favorable outcomes and supports the safety of lipid therapy. Current guidelines and case reports propose that a large bolus of lipid at the earliest signs of toxicity may prevent cardiovascular collapse. SUMMARY: As the obstetric demographic becomes older and more obese, new technologies and strategies can assist in controlling maternal death and major morbidity secondary to anesthesia complications. Lipid resuscitation appears to be an effective treatment for toxicity induced by lipophilic medications and may be useful in treating systemic toxicity in the pregnant patient. Obstetric care providers should be aware of lipid resuscitation and consider its use as described by American Society of Regional Anesthesia and Pain Medicine guidelines.

Intravenous lipid emulsion in clinical toxicology.

Intravenous lipid emulsion is an established, effective treatment for local anesthetic-induced cardiovascular collapse. The predominant theory for its mechanism of action is that by creating an expanded, intravascular lipid phase, equilibria are established that drive the offending drug from target tissues into the newly formed 'lipid sink'. Based on this hypothesis, lipid emulsion has been considered a candidate for generic reversal of toxicity caused by overdose of any lipophilic drug. Recent case reports of successful resuscitation suggest the efficacy of lipid emulsion infusion for treating non-local anesthetic overdoses across a wide spectrum of drugs: beta blockers, calcium channel blockers, parasiticides, herbicides and several varieties of psychotropic agents. Lipid emulsion therapy is gaining acceptance in emergency rooms and other critical care settings as a possible treatment for lipophilic drug toxicity. While protocols exist for administration of lipid emulsion in the setting of local anesthetic toxicity, no optimal regimen has been established for treatment of acute non-local anesthetic poisonings. Future studies will shape the evolving recommendations for lipid emulsion in the setting of non-local anesthetic drug overdose.