Related Experiment Video

Updated: Jun 23, 2025

Investigation of Genetic Dependencies Using CRISPR-Cas9-based Competition Assays
11:05

Investigation of Genetic Dependencies Using CRISPR-Cas9-based Competition Assays

Published on: January 7, 2019

9.5K

Aurkin-A, a TPX2-Aurora A small molecule inhibitor disrupts Alisertib-induced polyploidy in aggressive diffuse large

Patrick J Conway1, Bárbara De La Peña Avalos2, Jonathan Dao3

  • 1Department of Molecular Immunology & Microbiology, University of Texas Health Science Center San Antonio, 7703 Floyd Curl Drive, San Antonio, Texas, USA; Department of Biomedical Sciences, Keiser University, 2600 N Military Trl, West Palm Beach, Florida, USA.

Neoplasia (New York, N.Y.)
|June 14, 2024
PubMed

Insights

Alisertib, a cancer drug, can cause polyploidy, a form of drug resistance. Combining it with Aurkin A disrupts this polyploidy, increasing cancer cell death in Diffuse Large B Cell Lymphoma.

Area of Science:

  • Oncology
  • Cell Biology
  • Pharmacology

Background:

  • Chemotherapy can induce polyploidy, a mechanism of inherited drug resistance leading to aggressive cancer.
  • Alisertib, an Aurora Kinase A (AK-A) inhibitor, causes cell cycle disruption and polyaneuploidy in Diffuse Large B Cell Lymphoma (DLBCL).

Purpose of the Study:

  • To investigate the mechanism of alisertib-induced polyploidy in DLBCL.
  • To evaluate the efficacy of combining alisertib with Aurkin A, an AK-A/TPX2 inhibitor, in overcoming polyploidy and enhancing apoptosis.

Main Methods:

  • Quantification of alisertib-induced polyploidy using propidium iodide flow cytometry in U2932 and VAL cell lines.
  • Generation of a stable FUCCI U2932 cell line for monitoring cell cycle progression (Geminin-clover for S/G2/M, cdt1-mKO for G1).
  • Assessment of polyploidy and apoptosis in vitro and in vivo using a VAL mouse xenograft model.

Main Results:

  • Alisertib (1µM) induced 8n+ polyploidy in 48% of U2932 cells after 5 days.
  • Combination therapy with Aurkin A and alisertib dose-dependently disrupted alisertib-induced polyploidy and increased apoptosis.
  • Alisertib was found to induce polyploidy via endomitosis, a process reversed by Aurkin A treatment.
  • In vivo studies showed Aurkin A plus alisertib significantly reduced polyploidy in a VAL mouse xenograft model.

Conclusions:

  • Alisertib induces polyploidy in DLBCL through endomitosis, contributing to drug resistance.
  • Aurkin A synergizes with alisertib, reducing the required alisertib dose to disrupt polyploidy and increasing apoptosis.
  • Combination therapy with Aurkin A and alisertib presents a promising strategy to overcome chemoresistance in DLBCL.
Keywords:
AlisertibAneuploidyCell cycleChromosomal instabilityPolyploidy

More Related Videos

Intracellular Phosphoflow Cytometry of Acute Myeloid Leukemia Patient-Derived Xenotransplants07:39

Intracellular Phosphoflow Cytometry of Acute Myeloid Leukemia Patient-Derived Xenotransplants

Published on: June 6, 2025

73
Rapid Analysis of Chromosome Aberrations in Mouse B Lymphocytes by PNA-FISH07:54

Rapid Analysis of Chromosome Aberrations in Mouse B Lymphocytes by PNA-FISH

Published on: August 19, 2014

17.1K

Related Concept Videos

Abnormal Proliferation02:23

Abnormal Proliferation

Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the...
4.5K
Inhibition of Cdk Activity02:34

Inhibition of Cdk Activity

The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
4.7K
The Intrinsic Apoptotic Pathway01:31

The Intrinsic Apoptotic Pathway

Internal cellular stress, such as cellular injury or hypoxia, triggers intrinsic apoptosis. The B-cell lymphoma 2 (Bcl-2) family of proteins are the primary regulators of the intrinsic apoptotic pathway. For example, during DNA damage, checkpoint proteins, such as Ataxia Telangiectasia Mutated (ATM protein) and Checkpoints Factor-2 (Chk2) proteins, are activated. These proteins phosphorylate p53 which further activates pro-apoptotic proteins, such as Bax, Bak, PUMA, and Noxa, and inhibits...
6.5K
Targeted Cancer Therapies02:57

Targeted Cancer Therapies

The targeted cancer therapies, also known as “molecular targeted therapies,” take advantage of the molecular and genetic differences between the cancer cells and the normal cells. It needs a thorough understanding of the cancer cells to develop drugs that can target specific molecular aspects that drive the growth, progression, and spread of cancer cells without affecting the growth and survival of other normal cells in the body.
There are several types of targeted therapies against...
7.5K