Influence of survivin-targeted therapy on chemosensitivity in the treatment of acute myeloid leukemia

Abstract

Overexpression of survivin is observed in various hematological malignancies, including acute myeloid leukemia (AML). Studies show that elevated expression of survivin correlates with a worse clinic outcome in AML patients. It remains unclear whether inhibition of survivin may alter the efficacy of chemotherapy against AML. Here, we evaluate the effects of specific knockdown of survivin on AML cells’ sensitivity to chemotherapy, and investigate the therapeutic potential of the transcription inhibitor of survivin YM155 either alone or in combination with chemotherapeutic agents. We found Kasumi-1 and HL-60 cells had relatively higher expression levels of survivin among all AML cell lines tested. Specific knockdown of survivin in Kasumi-1 and HL-60 cells resulted in: inhibition of cell proliferation; cell cycle G2/M arrest; induction of DNA damage response and apoptosis. Downregulation of survivin enhanced etoposide- or doxorubicin-induced anti-proliferative/anti-survival activity in AML cells. The small molecule inhibitor YM155 reduced survivin in a dose- and time-dependent manner and trigged apoptosis in Kasumi-1 and HL-60 cells. The combinatorial effects of YM155 and chemotherapeutics were either synergetic or antagonistic, depending upon the drugs used for combination and the type of AML cells being treated. Collectively, our data demonstrate that survivin plays an important role in the maintenance and proliferation of AML cells. While specific knockdown of survivin enhances chemosensitivity, the combinations of YM155 and chemotherapeutic agents exhibit synergetic or antagonistic effects on AML cells. Our findings provide a rationale for further assessment of survivin-targeted therapy in the treatment of patients with AML.

MUC1‐C drives myeloid leukaemogenesis and resistance to treatment by a survivin‐mediated mechanism

“…These finding are consistent with previously published survival analysis using TCGA database demonstrating prolonged survival in AML patients with lower survivin expression . Furthermore, our analysis of this database of 168 adult AML patients confirmed that patients with low MUC1 expression showed significantly prolonged overall survival ( P = .02, data not shown).…”

MicroRNA-mediated epigenetic targeting of Survivin significantly enhances the antitumor activity of paclitaxel against non-small cell lung cancer

“…Lentiviral production was performed as described [17, 51]. In brief, the lentiviral expression vector pLKO.1-ConshRNA or pLKO.1-SurshRNA; pLEX-Luc or pLEX- hSurvivin ; miRZip control, miRZip-203, or miRZip-542-3p and the packaging plasmids psPAX2 and pMD2.G were co-transfected into HEK293T cells.…”

PERAN EKSPRESI p53 DAN SURVIVIN TERHADAP HEMOGLOBIN, LEUKOSIT, DAN TROMBOSIT PADA LEUKEMIA LIMFOBLASTIK AKUT ANAK YANG MENDAPATKAN KEMOTERAPI

“…Tingkat ketahanan sel yang menurun dapat diasumsikan sebagai peningkatan apoptosis yang dapat berkorelasi dengan penurunan ekspresi survivin. 15 Rendahnya nilai hemoglobin baik disebabkan karena adanya supresi sumsum tulang akibat proliferasi sel kanker, maupun karena adanya perdarahan akibat rendahnya trombosit sangat berpengaruh terhadap prognosis pasien. Penundaan pemberian kemoterapi akan berdampak pada overekspresi dari sel ganas, dan proliferasi multi organ.…”

“…Pasien dengan hemoglobin dan trombosit rendah memerlukan koreksi sebelum diberikan obat kemoterapi. 16 Pada 15 Prediksi terjadinya kemoresistensi menjadi perhatian yang penting dan pemantauan pada pasien LLA. Terdapat hubungan antara prognosis yang buruk dan adanya sel blast pada 10 hari setelah kemoterapi fase induksi yang telah banyak dipahami para klinisi sebagai dasar untuk memulai reinduksi.…”