Inhibitors of cyclin-dependent kinases CDK4 and CDK6 have been approved for treatment of hormone receptor–positive breast cancers. In contrast, triple-negative breast cancers (TNBCs) are resistant to CDK4/6 inhibition. Here, we demonstrate that a subset of TNBC critically requires CDK4/6 for proliferation, and yet, these TNBC are resistant to CDK4/6 inhibition due to sequestration of CDK4/6 inhibitors into tumor cell lysosomes. This sequestration is caused by enhanced lysosomal biogenesis and increased lysosomal numbers in TNBC cells. We developed new CDK4/6 inhibitor compounds that evade the lysosomal sequestration and are efficacious against resistant TNBC. We also show that coadministration of lysosomotropic or lysosome-destabilizing compounds (an antibiotic azithromycin, an antidepressant siramesine, an antimalaria compound chloroquine) renders resistant tumor cells sensitive to currently used CDK4/6 inhibitors. Lastly, coinhibition of CDK2 arrested proliferation of CDK4/6 inhibitor-resistant cells. These observations may extend the use of CDK4/6 inhibitors to TNBCs that are refractory to current anti-CDK4/6 therapies.
Extruded cereal snacks are usually deficient in protein, mineral ingredients, valuable fatty acids. With the rise of health awareness among consumers, food manufacturers and scientists are pressed to take measures in order to develop new functional/health-beneficial foods. The aim of this work was to manufacture extruded crisps enriched with α-linolenic acid (obtained from linseed oil) and to observe whether storage of the product for the period of 6 months would cause its disqualification, primarily due to its sensory properties and secondarily due to its chemical properties. The research demonstrated that the addition of linseed oil to corn crisps at the amount of 5 % enables to obtain functional corn crisps containing over 2 g of ALA in a portion of 100 g even after 6 months of storage at room temperature. ALA-enriched crisps maintain the original sensory profile after 6 months of storage and their sensory profile is similar to the profile of crisps without the addition of linseed oil if they are packed in barrier packaging filled 100 % with argon. Therefore, they may be a healthier alternative to typical corn crisps.Electronic supplementary materialThe online version of this article (doi:10.1007/s11746-016-2873-y) contains supplementary material, which is available to authorized users.
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