TY - JOUR
T1 - Aurkin-A, a TPX2-aurora a small molecule inhibitor disrupts Alisertib-induced polyploidy in aggressive diffuse large B cell lymphoma
AU - Conway, Patrick J.
AU - De La Peña Avalos, Bárbara
AU - Dao, Jonathan
AU - Montagnino, Sebastian
AU - Kovalskyy, Dmytro
AU - Dray, Eloise
AU - Mahadevan, Daruka
N1 - Publisher Copyright:
© 2024
PY - 2024/9
Y1 - 2024/9
N2 - Chemotherapy induced polyploidy is a mechanism of inherited drug resistance resulting in an aggressive disease course in cancer patients. Alisertib, an Aurora Kinase A (AK-A) ATP site inhibitor, induces cell cycle disruption resulting in polyaneuploidy in Diffuse Large B Cell Lymphoma (DLBCL). Propidium iodide flow cytometry was utilized to quantify alisertib induced polyploidy in U2932 and VAL cell lines. In U2932 cells, 1µM alisertib generated 8n+ polyploidy in 48% of the total cell population after 5 days of treatment. Combination of Aurkin A an AK-A/TPX2 site inhibitor, plus alisertib disrupted alisertib induced polyploidy in a dose-dependent manner with associated increased apoptosis. We generated a stable FUCCI U2932 cell line expressing Geminin-clover (S/G2/M) and cdt1-mKO (G1), to monitor cell cycle progression. Using this system, we identified alisertib induces polyploidy through endomitosis, which was eliminated with Aurkin A treatment. In a VAL mouse xenograft model, we show polyploidy generation in alisertib treated mice versus vehicle control or Aurkin A. Aurkin A plus alisertib significantly reduced polyploidy to vehicle control levels. Our in vitro and in vivo studies show that Aurkin A synergizes with alisertib and significantly decreases the alisertib dose needed to disrupt polyploidy while increasing apoptosis in DLBCL cells.
AB - Chemotherapy induced polyploidy is a mechanism of inherited drug resistance resulting in an aggressive disease course in cancer patients. Alisertib, an Aurora Kinase A (AK-A) ATP site inhibitor, induces cell cycle disruption resulting in polyaneuploidy in Diffuse Large B Cell Lymphoma (DLBCL). Propidium iodide flow cytometry was utilized to quantify alisertib induced polyploidy in U2932 and VAL cell lines. In U2932 cells, 1µM alisertib generated 8n+ polyploidy in 48% of the total cell population after 5 days of treatment. Combination of Aurkin A an AK-A/TPX2 site inhibitor, plus alisertib disrupted alisertib induced polyploidy in a dose-dependent manner with associated increased apoptosis. We generated a stable FUCCI U2932 cell line expressing Geminin-clover (S/G2/M) and cdt1-mKO (G1), to monitor cell cycle progression. Using this system, we identified alisertib induces polyploidy through endomitosis, which was eliminated with Aurkin A treatment. In a VAL mouse xenograft model, we show polyploidy generation in alisertib treated mice versus vehicle control or Aurkin A. Aurkin A plus alisertib significantly reduced polyploidy to vehicle control levels. Our in vitro and in vivo studies show that Aurkin A synergizes with alisertib and significantly decreases the alisertib dose needed to disrupt polyploidy while increasing apoptosis in DLBCL cells.
KW - Alisertib
KW - Aneuploidy
KW - Cell cycle
KW - Chromosomal instability
KW - Polyploidy
UR - http://www.scopus.com/inward/record.url?scp=85195878664&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85195878664&partnerID=8YFLogxK
U2 - 10.1016/j.neo.2024.101014
DO - 10.1016/j.neo.2024.101014
M3 - Article
C2 - 38875929
AN - SCOPUS:85195878664
SN - 1522-8002
VL - 55
JO - Neoplasia (United States)
JF - Neoplasia (United States)
M1 - 101014
ER -