Original Research ARTICLE
Front. Pharmacol., 29 January 2020 | https://doi.org/10.3389/fphar.2019.01658
Berberine Maintains the Neutrophil N1 Phenotype to Reverse Cancer Cell Resistance to Doxorubicin
This study explores the contributions of neutrophils to chemotherapeutic resistance and berberine-regulated cancer cell sensitivity to doxorubicin (DOX). In vitro experiments, continuous DOX treatment led to the shift of HL-60 cells to N2 neutrophils and thus induced chemotherapeutic resistance. The combination treatment with DOX and 2 µM berberine resulted in the differentiation of HL-60 cells toward N1 and therefore stimulated HL-60 cell immune clearance. Berberine increased reactive oxygen species (ROS) and decreased autophagy and therefore induced apoptosis in HL-60-N2 cells with morphological changes, but had no effect on cell viability in HL-60-N1 cells. The neutrophil-regulating efficacy of berberine was confirmed in the urethane-induced lung carcinogenic model and H22 liver cancer allograft model. Furthermore, we found that DOX-derived neutrophils had high levels of CD133 and CD309 surface expression, which prevented both chemotherapeutic sensitivity and immune rejection by self-expression of PD-L1 and surface expression of PD-1 receptor on T cells, whereas berberine could downregulate CD133 and CD309 surface expression. Finally, berberine-relevant targets and pathways were evaluated. This study first suggests an important role of berberine in regulating neutrophil phenotypes to maintain cancer cell sensitivity to DOX.Ur studien saxar jag det PHI-relevanta.
Materials and Methods
For the morphological assessment, cells were analyzed by a laser holographic cell imaging and analysis system (HoloMonitor M4, Phiab, Sweden).
For the time-lapse migration assay, cells were placed onto a motorized stage and observed with a laser holographic cell imaging and analysis system (HoloMonitor M4, Phiab, Sweden).
A 20× objective was used to capture images during the course of the time-lapse.
Images were captured every 15 s over the course of 30 min from at least four different fields of view.
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| Lägg till bildtext |
N1-like and N2-like neutrophils showed different phenotypic characteristics in stemness, mobility and jak2/stat3 signaling. (A) Cell protein expression of CD309, CD133, and PD-L1 indicated by immunofluorescence (n = 5, 40×). (B–D) Immunofluorescence score of (A) (n = 5). (E) Cell mobility observed by a laser holographic cell imaging and analysis system (n = 5, 20×). (F) The quantitative value of (E) (n = 5). (G) Protein expression levels of jak2/stat3 examined by Western blotting (n = 5). The data present mean ± SD, the experiments were repeated three times, and statistical significance was determined by a t-test. (B–D, F) *P < 0.05, **P < 0.01 vs. HL60; #P < 0.05, ##P < 0.01 vs. HL60-N2. (G) *P < 0.05, **P < 0.01 vs. HL60-N2+BER; #P < 0.05, ##P < 0.01 vs. HL60-N2. DOX, doxorubicin; BER, berberine.
Min kommentar
Studien är mycket intressant då den tar upp ett problem läkarkåren ibland ställs inför.
Vad händer när cancerpatient inte längre "svarar" på insatt cancerläkemedel?
Att kroppen har utvecklat resistens mot det givna medlet.
I denna studie kikar man närmare på resistens mot det vanliga cancerläkemedlet Doxorubicin.
Dox är ett vanligt förekommande läkemedel för drabbade cancerpatienter.
Svenska fass berättar mer :
Doxorubicin Ebewe, som innehåller det aktiva ämnet doxorubicin, tillhör en grupp läkemedel som kallas antracykliner och är ett läkemedel mot cancer. Läkemedlet verkar genom att sakta av eller stoppa tillväxten av cancerceller.Doxorubicin Ebewe används ofta i kombination med andra läkemedel mot cancer.
Doxorubicin Ebewe kan användas vid behandling mot bland annat följande cancerformer:
bröstcancer,cancer i bindväv, ledband, skelett och muskler (sarkom)lungcancer,cancer i lymfkörtlar (Hodgkins sjukdom och maligna non-Hodgkinlymfom),cancer i blodet (akut leukemi),benmärg (myelom),cancer i prostata eller testiklarna,sköldkörtelcancer,cancer i äggstockarna eller livmodern,
cancer i urinblåsan,cancer i huvud/hals,magcancer,tumörer hos barn såsom neuroblastom,
rhabdomyosarkom, Wilms tumör.
Dox godkändes som cancerläkemedel 1974 och finns med på WHO`s lista över de mest säkra och effektiva läkemedel sjukvården kan använda sig av.
Av den anledningen är det bekymmersamt att cancerpatienter utvecklar resistens mot medlet.
Så dessa kinesiska forskare tog sig an detta problem för läkarkåren och naturligtvis cancerpatienters fromma.
I studien,som man kan anta har varit tämligen omfattande,har man vänt sig till stamcellsforskning.
Alltså gått ner på gennivå och studerat effekter tillsatta ämnen haft för att häva resistensen.
Man hittade 1 effektivt ämne,nämligen berberin (Rhizoma Coptis),som utvinns ur växter.
Ämnet är sen tidigare känt för sin förmåga att förändra molekylstrukturen inuti en cell.
"Berberine can create changes within the molecules of cells, and this could have another potential benefit: fighting cancer."
Forskarna följde sedan ämnets inverkan vid olika styrkor/koncentration av läkemedlet Dox.
Man observerade de olika försöken via HoloMonitor,hur celler reagerade.
Och slutligen hittade man rätt i studierna. Lättförståligt förklarat i denna slutsats:
"Furthermore, we found that DOX-derived neutrophils had high levels of CD133 and CD309 surface expression, which prevented both chemotherapeutic sensitivity and immune rejection by self-expression of PD-L1 and surface expression of PD-1 receptor on T cells, whereas berberine could downregulate CD133 and CD309 surface expression. Finally, berberine-relevant targets and pathways were evaluated. This study first suggests an important role of berberine in regulating neutrophil phenotypes to maintain cancer cell sensitivity to DOX.
In summary, tumor- and chemotherapy-induced N2-type neutrophils play a crucial role in cancer cell resistance to DOX, and our findings suggest several potential clinical implications. First, N2 neutrophil accumulation correlates with cancer progression and cancer cell resistance to chemotherapy, supporting TINs as a therapeutic target to promote DOX-based chemosensitivity. Second, alteration of the neutrophil phenotype is superior to depletion of TINs for reversing chemoresistance and immune escape, indicating the potential of re-educating these cells to reverse their pro-tumor functions for anti-tumor properties. Third, neutrophils, as the first responders of innate immune surveillance, can not only enhance tumor cell susceptibility to chemotherapy but also restore the function of exhausted T cells, providing a novel strategy for resolving the contradiction between chemotherapy-induced immunological cytotoxicity and immune system-induced tumor rejection. Certainly, whether re-educating TINs is the most effective approach for reversing the immunosuppressive environment needs to be fully evaluated.
HoloMonitor firar ånyo triumf som en forskares oundgängliga verktyg att nå nya insikter.
Tack för allt jobb du lägger ner.
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