The Resistance of Cancer Cells to Palbociclib, a Cyclin-Dependent Kinase 4/6 Inhibitor, is Mediated by the ABCB1 Transporter.

Palbociclib was approved by the United States Food and Drug Administration for use, in combination with letrozole, as a first-line treatment for estrogen receptor-positive/human epidermal growth factor receptor 2-negative (ER+/HER2-) postmenopausal metastatic breast cancer. However, recent studies show that palbociclib may be an inhibitor of the ABCB1 transporter, although this remains to be elucidated. Therefore, we conducted experiments to determine the interaction of palbociclib with the ABCB1 transporter. Our in vitro results indicated that the efficacy of palbociclib was significantly decreased in the ABCB1-overexpressing cell lines. Furthermore, the resistance of ABCB1-overexpressing cells to palbociclib was reversed by 3 µM of the ABCB1 inhibitor, verapamil. Moreover, the incubation of ABCB1-overexpressing KB-C2 and SW620/Ad300 cells with up to 5 µM of palbociclib for 72 h, significantly upregulated the protein expression of ABCB1. The incubation with 3 µM of palbociclib for 2h significantly increased the intracellular accumulation of [3H]-paclitaxel, a substrate of ABCB1, in ABCB1 overexpressing KB-C2 cells but not in the corresponding non-resistant parental KB-3-1 cell line. However, the incubation of KB-C2 cells with 3 µM of palbociclib for 72 h decreased the intracellular accumulation of [3H]-paclitaxel due to an increase in the expression of the ABCB1 protein. Palbociclib produced a concentration-dependent increase in the basal ATPase activity of the ABCB1 transporter (EC50 = 4.73 µM). Molecular docking data indicated that palbociclib had a high binding affinity for the ABCB1 transporter at the substrate binding site, suggesting that palbociclib may compete with other ABCB1 substrates for the substrate binding site of the ABCB1. Overall, our results indicate that palbociclib is a substrate for the ABCB1 transporter and that its in vitro anticancer efficacy is significantly decreased in cancer cells overexpressing the ABCB1.

[Detection of mite allergens in the dust of filter-net and air of air-conditioned room].

OBJECTIVE: To detect mite allergens in the dust of air conditioner filter-net and floating air in room. METHODS: Samples were collected from rooms of asthma patient and normal families with or without air conditioner. Der p1, Der f1 and Der 2 were determined by two monoclonal antibody-based ELISA. RESULTS: In asthma patient families, the concentration of airborne Der p1, Der f1 and Der 2 was (0.23 +/- 0.13), (2.62 +/- 1.08), (0.93 +/- 0.41) ng/m3, and (0.56 +/- 0.25), (4.74 +/- 1.22), (2.33 +/- 0.64) ng/m3 respectively before and after the air conditioner switched on, all showing a significant difference (P < 0.05). In families without asthma patient, the concentration of Der p1, Der f1 and Der 2 was (0.33 +/- 0.11), (11.50 +/- 3.08) and (2.10 +/- 0.80) ng/m3, and (0.63 +/- 0.23), (19.80 +/- 4.30) and (3.60 +/- 1.00) ng/m3 respectively before and after the air conditioner switched on, also showing a significant difference (P < 0.05). From the filter-net dust of air conditioner in family with allergic asthma patient, the concentration of Der p1, Der f1 and Der 2 was (0.52 +/- 0.19), (3.34 +/- 0.63), (2.53 +/- 0.65) microg/g dust, while that of normal families was (1.30 +/- 0.35), (5.16 +/- 0.92), (3.47 +/- 1.13) microg/g dust respectively. The concentration of Der f1 and Der 2 at both asthma families and normal families was higher than 2 microg/g, an allergen concentration threshold. CONCLUSION: Mite allergens exist in the filter-net dust of air conditioner, which may be an important source of indoor allergens and a cause of the increasing prevalence of allergic asthma.

Detection of Dermatophagoides farinae in the dust of air conditioning filters.

BACKGROUND: The allergenic dust mite species Dermatophagoides pteronyssinus and Dermatophagoides farinae generally inhabit warm moist environments. This study tested the hypothesis that these allergenic species may thrive in air conditioner filters. METHODS: A year-long investigation of the dust mite population densities and species identities living in air conditioner filters in Shenzhen City in Southern China was performed. Additional data describing the levels of major dust mite allergen proteins from samples collected in July and August 2004 were analyzed. Genetic polymorphism analysis of Der f 1 and Der f 2 genes in the collected animals was also conducted. RESULTS: Our investigation revealed that larval dust mites started to grow in March, from which time their populations proceeded to steadily increase until reaching their population zenith in July and August. The dust mite populations decreased sharply in October and live dust mites were no longer observed in the winter. Among the mites collected in July and August, 30.1 and 25.8% were of the species D. farinae. The concentration of Der f 1 was 3.04 +/- 1.75 and 3.21 +/- 1.84 microg/g dust in July and August, respectively, and that of Der f 2 was 2.15 +/- 0.82 and 2.04 +/- 1.15 microg/g dust. Four types of Der f 1 and 5 types of Der f 2 cDNA sequences were cloned from collected Der f mites. Their sequences were highly homologous with those previously published in GenBank (No. AB034946.1 and No. AB195580.1). CONCLUSIONS: This research demonstrated that Der f allergens exist in the dust of air conditioner filters in this area.