Abstract 6340: Re-sensitization of irinotecan/SN38 resistant colorectal cancer cells by SCO-101

Introduction: Annually, more than 1 million people are diagnosed with Colorectal Cancer (CRC) and more than 500.000 die from CRC. Only three types of chemotherapy are currently being used worldwide to treat CRC patients: 5FU, oxaliplatin and irinotecan. However, chemotherapy resistance is present or...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Cancer research (Chicago, Ill.) Ill.), 2020-08, Vol.80 (16_Supplement), p.6340-6340
Hauptverfasser: Stenvang, Jan, Ambjørner, Sophie, Sedighi, Khwajanezrabodin, Vestlev, Peter Michael, Saaby, Lasse, Brodin, Birger, Brunner, Nils
Format: Artikel
Sprache:eng
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
Beschreibung
Zusammenfassung:Introduction: Annually, more than 1 million people are diagnosed with Colorectal Cancer (CRC) and more than 500.000 die from CRC. Only three types of chemotherapy are currently being used worldwide to treat CRC patients: 5FU, oxaliplatin and irinotecan. However, chemotherapy resistance is present or develops in the majority of metastatic CRC patients. Resistance to anti-cancer drugs represents the main cause of cancer-related deaths. Thus, re-sensitization of chemotherapy resistant cancer cells constitutes a highly unmet medical need. Materials and Methods: The drug, SCO-101, is an oral drug and has previously passed 4 Phase I clinical trials where it demonstrated excellent PK (T1/2=15 hours) and favourable safety profile. We used two pairs of parental (sensitive) and SN38-resistant (SN38 is the active metabilote of irinotecan) human colon cancer cell lines (HT29 and LoVo). Cell viability in vitro during 72h exposure to SCO-101 and/or SN38 was adressed by MTT assays. The level of the SN38 efflux transpoter, ABCG2/BCRP, was investigated in the presence or absence of SCO-101. Additionally, various flux assays were applied to investigate the effect of SCO-101 on ABCG2/BCRP activity. A kinase screen revealed that the kinase SRPK1 was inhibited by SCO-101 and the importance of SRPK1 activity in re-sensitization of SN38 resistant colon cancer cells was investigated by two different synthetic SRPK1 inhbitors. Results: In parental HT29 and LoVo cells, SCO-101 and SN38 each had a dose-dependent effect on cell viability and no combinational effects were observed between the drugs. When exposing SN38-resistant cells to the combination of SCO-101 and SN38, a significant inhibitory effect on cell viability compared to either drug alone was observed, suggesting an additive or synergistic effect between these two drugs with SCO-101 re-sensitizing the resistant cells to SN38. Flux assays with ABCG2 /BCRP substrates clearly demonstrated that SCO-101 inhibited the activity of ABCG2 and protein analysis further demonstrated that SCO-101 causes degradation of ABCG2/BCRP. Cell viability assays with two different SRPK1 inhibitors demonstrated that this kinase is involved in re-sensitization to SN38. Conclusion and future perspectives: These preclinical studies demonstrate that SCO-101 sensitizes SN38-resistant colon cancer cells to SN38 through two different mechanisms of actions e.g. inhibition of the SRPK1 kinase and degradation of the ABCG2/BCRP drug efflux pump. We are now
ISSN:0008-5472
1538-7445
DOI:10.1158/1538-7445.AM2020-6340