3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) inhibitors, commonly known as statins, may possess cancer preventive and therapeutic properties. Statins are effective suppressors of cholesterol synthesis with a well-established risk-benefit ratio in cardiovascular disease prevention. Mechanistically, targeting HMGCR activity primarily influences cholesterol biosynthesis and prenylation of signaling proteins. Pravastatin is a hydrophilic statin that is selectively taken up by a sodium-independent organic anion transporter protein-1B1 (OATP1B1) exclusively expressed in liver. Simvastatin is a hydrophobic statin that enters cells by other mechanisms. Poorly-differentiated and well-differentiated cancer cell lines were selected from various tissues and examined for their response to these two statins. Simvastatin inhibited the growth of most tumor cell lines more effectively than pravastatin in a dose dependent manner. Poorly-differentiated cancer cells were generally more responsive to simvastatin than well-differentiated cancer cells, and the levels of HMGCR expression did not consistently correlate with response to statin treatment. Pravastatin had a significant effect on normal hepatocytes due to facilitated uptake and a lesser effect on prostate PC3 and colon Caco-2 cancer cells since the OATP1B1 mRNA and protein were only found in the normal liver and hepatocytes. The inhibition of cell growth was accompanied by distinct alterations in mitochondrial networks and dramatic changes in cellular morphology related to cofilin regulation and loss of p-caveolin. Both statins, hydrophilic pravastatin and hypdrophobic simvastatin caused redistribution of OATP1B1 and HMGCR to perinuclear sites. In conclusion, the specific chemical properties of different classes of statins dictate mechanistic properties which may be relevant when evaluating biological responses to statins.

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BackgroundCeramide synthesis and metabolism is a promising target in cancer drug development. γ-tocotrienol (GT3), a member of the vitamin E family, orchestrates multiple effects that ensure the induction of apoptosis in both, wild-type and RAS-mutated pancreatic cancer cells. Here, we investigated whether these effects involve changes in ceramide synthesis and transport.MethodsThe effects of GT3 on the synthesis of ceramide via the de novo pathway, and the hydrolysis of sphingomyelin were analyzed by the expression levels of the enzymes serine palmitoyl transferase, ceramide synthase-6, and dihydroceramide desaturase, and acid sphingomyelinase in wild-type RAS BxPC3, and RAS-mutated MIA PaCa-2 and Panc 1 pancreatic cancer cells. Quantitative changes in ceramides, dihydroceramides, and sphingomyelin at the cell membrane were detected by LCMS. Modulation of ceramide transport by GT3 was studied by immunochemistry of CERT and ARV-1, and the subsequent effects at the cell membrane was analyzed via immunofluorescence of ceramide, caveolin, and DR5.ResultsGT3 favors the upregulation of ceramide by stimulating synthesis at the ER and the plasma membrane. Additionally, the conversion of newly synthesized ceramide to sphingomyelin and glucosylceramide at the Golgi is prevented by the inhibition of CERT. Modulation ARV1 and previously observed inhibition of the HMG-CoA pathway, contribute to changes in membrane structure and signaling functions, allows the clustering of DR5, effectively initiating apoptosis.ConclusionsOur results suggest that GT3 targets ceramide synthesis and transport, and that the upregulation of ceramide and modulation of transporters CERT and ARV1 are important contributors to the apoptotic properties demonstrated by GT3 in pancreatic cancer cells.

In recent years, several new oral anticancer drugs have been approved, many via an accelerated approval process. These new agents have the potential for drug interactions, but lack of familiarity with these drugs by clinicians may increase the risk for drug interactions. We describe an interaction between the new anticancer agent idelalisib (CYP 3A4 inhibitor) and diazepam (CYP 3A4 substrate) that resulted in altered mental status and type II respiratory failure resulting in hospitalization. After discontinuation of both agents, the patient recovered quickly. Idelalisib was reinitiated after discharge. Lorazepam was substituted for diazepam since it is not metabolized via CYP 3A4. Both agents were tolerated well thereafter. This interaction was only flagged by two of four commonly used drug interaction databases. Clinicians should exercise caution with initiating new oral anticancer agents and consider the potential for drug interactions without solely relying on drug interaction databases.

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Survivorship care for a patient with cancer is often complex and requires a multidisciplinary approach. Cancer and its treatment can have late and long-term physical and psychosocial effects. After the acute and intense period of treatment and surveillance administered by oncology teams, cancer survivors slowly transition care to primary providers. Cancer survivors then enter into an extended phase of survivorship whether they are cancer-free, in remission, or living with cancer. In this phase, symptoms related to cancer and its treatment may vary over time. Developing a care plan can facilitate the transition of care between all providers taking care of cancer patients.

COVID-19 is an infectious disease caused by the novel coronavirus. It presents as an acute respiratory illness, however, it also affects multiple other organ systems. One such unique manifestation is systemic coagulopathy involving arterial and venous systems. We present a 29-year-old woman with Hodgkin’s lymphoma, who was diagnosed with COVID-19 infection prior to initiating chemotherapy. Two months after resolution of symptoms and testing negative for COVID-19, she presented with multiple acute thromboembolic complications of the infection, including bilateral jugular venous thrombosis, right atrial clot and arterial emboli in the brain resulting in cerebrovascular injury. These were thought to be delayed manifestations of the systemic coagulopathy secondary to infection. Also, some of these thromboembolic phenomena occurred while the patient was on anticoagulation, which emphasises the extensive hyperinflammatory state caused by the virus. This case highlights the importance of thromboprophylaxis especially in high-risk patients with this infection.