Related Experiment Video

Updated: Jul 21, 2025

Pooled shRNA Library Screening to Identify Factors that Modulate a Drug Resistance Phenotype
14:51

Pooled shRNA Library Screening to Identify Factors that Modulate a Drug Resistance Phenotype

Published on: June 17, 2022

3.3K

Genetic and chemical targeting of the ATPase complex TIP48 and 49 impairs acute myeloid leukemia

Ayuna Hattori1,2, Emi Takamatsu-Ichihara3, Yoshiki Yamamoto4

  • 1Division of Hematological Malignancy, National Cancer Center Research Institute, Tokyo, Japan. ayu.hattori@infront.kyoto-u.ac.jp.

Leukemia
|July 25, 2023
PubMed

Insights

Loss of Tip48/49 ATPases triggers cancer cell death and inhibits leukemia. A novel compound, DS-4950, targeting these ATPases shows promise for treating various human cancers.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Biochemistry

Background:

  • Chromatin-associated AAA+ ATPases Tip48 and Tip49 are crucial for nuclear events.
  • Overexpression of Tip48/49 is common in human cancers, but their role is unclear.

Purpose of the Study:

  • To investigate the functional significance of Tip48/49 in cancer.
  • To develop and evaluate a novel inhibitor of Tip48/49 ATPase activity for cancer therapy.

Main Methods:

  • Investigated the effects of Tip49 loss on leukemia development in vivo.
  • Developed and administered DS-4950, a chemical inhibitor of Tip48/49 ATPase activity.
  • Assessed tumor burden, survival rates, and p53 dependency in cancer models.

Main Results:

  • Loss of Tip49 induced p53-dependent apoptosis and suppressed leukemia.
  • DS-4950 treatment was well-tolerated in mice, reduced tumor burden, and improved survival.
  • Tip48/49 dependency was observed in non-hematologic wild-type p53 malignancies.

Conclusions:

  • Tip48/49 ATPases are essential for cancer cell survival and proliferation.
  • Targeting Tip48/49 with inhibitors like DS-4950 represents a viable therapeutic strategy for human cancers.

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

174
Pre-clinical Evaluation of Tyrosine Kinase Inhibitors for Treatment of Acute Leukemia10:49

Pre-clinical Evaluation of Tyrosine Kinase Inhibitors for Treatment of Acute Leukemia

Published on: September 18, 2013

18.2K

Related Concept Videos

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...
7.7K
Combination Therapies and Personalized Medicine02:50

Combination Therapies and Personalized Medicine

Combining two or more treatment methods increases the life span of cancer patients while reducing damage to vital organs or tissue from the overuse of a single treatment. Combination therapy also targets different cancer-inducing pathways, thus reducing the chances of developing resistance to treatment.
The combination of the drug acetazolamide and sulforaphane is a good example of combination therapy to treat cancer. The cells in the interior of a large tumor often die due to the hypoxic and...
4.9K
ATP Synthase: Mechanism01:48

ATP Synthase: Mechanism

In animals, the mitochondrial F1F0 ATP synthase is the key protein that synthesizes ATP molecules through a complex catalytic mechanism. While the nuclear genome encodes the majority of ATP synthase subunits, the mitochondrial genome encodes some of the enzyme's most critical components. The formation of this multi-subunit enzyme is a complex multi-step process regulated at the level of transcription, translation, and assembly. Defects in one or more of these steps can result in decreased...
14.8K
Treatment Resistant Cancers02:56

Treatment Resistant Cancers

Cancer is the second leading cause of death in the United States. A cancer cell is genetically unstable and hence can mutate faster. They can also modify their microenvironment and escape immune surveillance. The difficulties in treating cancer are further compounded by the emergence of rapid resistance to anticancer drugs. The most common ways to attain resistance in cancer cells include alteration in drug transport and metabolism, modification of drug target, elevated DNA damage response, or...
3.3K
Electron Transport Chain: Complex I and II01:46

Electron Transport Chain: Complex I and II

The mitochondrial electron transport chain (ETC) is the main energy generation system in the eukaryotic cells. However, mitochondria also produce cytotoxic reactive oxygen species (ROS) due to the large electron flow during oxidative phosphorylation. While Complex I is one of the primary sources of superoxide radicals, ROS production by Complex II is uncommon and may only be observed in cancer cells with mutated complexes.
ROS generation is regulated and maintained at moderate levels necessary...
14.5K
Drugs that Destabilize Microtubules01:10

Drugs that Destabilize Microtubules

Microtubules are dynamic structures and can be regulated by microtubule targeting agents (MTAs). Microtubule destabilizing drugs are a class of MTAs that destabilize and prevent microtubules' polymerization. Both natural and synthetic chemicals can be found under this class of drugs. Vincristine and vinblastine, two vinca alkaloids, and colchicine were among the first to be discovered. These drugs can affect cells in various ways, either by inducing a change in cell morphology, preventing...
2.0K