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Related Concept Videos

Targeted Cancer Therapies02:57

Targeted Cancer Therapies

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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...
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Inhibition of Cdk Activity02:34

Inhibition of Cdk Activity

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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...
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Combination Therapies and Personalized Medicine02:50

Combination Therapies and Personalized Medicine

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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...
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The Intrinsic Apoptotic Pathway01:31

The Intrinsic Apoptotic Pathway

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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...
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Abnormal Proliferation02:23

Abnormal Proliferation

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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...
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Mitogens and the Cell Cycle02:38

Mitogens and the Cell Cycle

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Mitogens and their receptors play a crucial role in controlling the progression of the cell cycle. However, the loss of mitogenic control over cell division leads to tumor formation. Therefore, mitogens and mitogen receptors play an important role in cancer research. For instance, the epidermal growth factor (EGF) - a type of mitogen and its transmembrane receptor (EGFR), decides the fate of the cell's proliferation. When EGF binds to EGFR, a member of the ErbB family of tyrosine kinase...
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Related Experiment Video

Updated: Mar 14, 2026

Methods for Evaluating the Role of c-Fos and Dusp1 in Oncogene Dependence
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Methods for Evaluating the Role of c-Fos and Dusp1 in Oncogene Dependence

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The Myocyte-Damaging Effects of the BCR-ABL1-Targeted Tyrosine Kinase Inhibitors Increase with Potency and Decrease

Brian B Hasinoff1, Daywin Patel2, Xing Wu2

  • 1College of Pharmacy, Apotex Centre, University of Manitoba, 750 McDermot Avenue, Winnipeg, MB, R3E 0T5, Canada. B_Hasinoff@UManitoba.ca.

Cardiovascular Toxicology
|October 4, 2016
PubMed
Summary

Cardiovascular toxicity from BCR-ABL1 inhibitors is linked to direct ABL1 inhibition and off-target effects. Specific inhibitors caused less myocyte damage, while less specific ones caused more, correlating with clinical toxicity.

Keywords:
BosutinibCardiac myocytesCardiotoxicityChronic myelogenous leukemiaDasatinibImatinib mesylateNilotinibPonatinibTyrosine kinase inhibitor

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A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors
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A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors

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

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

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Area of Science:

  • Pharmacology
  • Cardiology
  • Oncology

Background:

  • BCR-ABL1 tyrosine kinase inhibitors (TKIs) treat chronic myelogenous leukemia.
  • Cardiotoxicity is a known side effect of these TKIs, with unclear mechanisms.
  • Conflicting data exists on whether cardiotoxicity stems from on-target (ABL1 inhibition) or off-target effects.

Purpose of the Study:

  • To investigate the relative cardiotoxicity of five clinically approved BCR-ABL1 TKIs.
  • To determine if TKI-induced myocyte damage is due to on-target ABL1 inhibition or off-target kinase activity.
  • To correlate in vitro myocyte damage with clinical cardiovascular toxicity.

Main Methods:

  • Utilized a neonatal rat myocyte model to assess TKI-induced myocyte damage.
  • Assessed growth inhibition of K562 cells (BCR-ABL1 positive) by TKIs.
  • Correlated myocyte damage with TKI specificity, potency, and dissociation binding constants.

Main Results:

  • Least specific and most potent TKIs (ponatinib, dasatinib) induced the most myocyte damage.
  • Most specific and least potent TKIs (imatinib, nilotinib) induced the least myocyte damage.
  • Myocyte damage correlated with clinical cardiovascular toxicity and inhibitor selectivity.

Conclusions:

  • TKI-induced myocyte damage is influenced by both direct ABL1 inhibition and off-target effects.
  • Lack of kinase selectivity contributes significantly to TKI cardiotoxicity.
  • Understanding these mechanisms can inform safer TKI development for leukemia treatment.