Related Experiment Video

Updated: Aug 15, 2026

Enhancement of Apoptotic and Autophagic Induction by a Novel Synthetic C-1 Analogue of 7-deoxypancratistatin in Human Breast Adenocarcinoma and Neuroblastoma Cells with Tamoxifen
19:44

Enhancement of Apoptotic and Autophagic Induction by a Novel Synthetic C-1 Analogue of 7-deoxypancratistatin in Human Breast Adenocarcinoma and Neuroblastoma Cells with Tamoxifen

Published on: May 30, 2012

Abrogation of mitochondrial cytochrome c release and caspase-3 activation in acquired multidrug resistance

H Kojima1, K Endo, H Moriyama

  • 1Department of Otolaryngology, The Jikei University School of Medicine, Tokyo 105, Japan.

The Journal of Biological Chemistry
|June 27, 1998
PubMed

Insights

Acquired multidrug resistance in cancer cells is linked to Bcl-xL protein overexpression. This blocks apoptosis by inhibiting mitochondrial cytochrome c release, a new resistance mechanism against various anti-cancer drugs.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Acquired multidrug resistance (MDR) in cancer is a significant clinical challenge.
  • Overexpression of P-glycoprotein and ATP-binding cassette superfamily members are known MDR mechanisms.
  • The role of anti-apoptotic proteins in MDR requires further elucidation.

Purpose of the Study:

  • To investigate the role of Bcl-xL in acquired multidrug resistance.
  • To determine the impact of Bcl-xL overexpression on apoptosis induction by anti-cancer drugs.
  • To identify the specific mechanism by which Bcl-xL confers resistance.

Main Methods:

  • Selection of SCC-25 cells for resistance to cisplatin (CDDP).
  • Analysis of apoptosis markers (caspase-3, protein kinase C delta) in resistant vs. parental cells.
  • Assessment of mitochondrial cytochrome c release in response to CDDP and ara-C.
  • Evaluation of apoptosis induction upon addition of cytochrome c to resistant cell lysates.

Main Results:

  • CDDP-resistant SCC-25 cells overexpressed Bcl-xL and resisted apoptosis.
  • Resistant cells failed to activate caspase-3 or cleave protein kinase C delta upon CDDP or ara-C treatment.
  • Multidrug-resistant cells (selected with doxorubicin, vincristine) also overexpressed Bcl-xL and showed resistance.
  • A block in mitochondrial cytochrome c release into the cytosol was observed in Bcl-xL overexpressing cells.
  • Addition of cytochrome c to resistant cell lysates restored caspase-3 activation, confirming the release block.

Conclusions:

  • Overexpression of Bcl-xL is a common response to diverse anti-cancer drugs, contributing to acquired multidrug resistance.
  • Bcl-xL confers resistance by inhibiting the release of mitochondrial cytochrome c, thereby blocking apoptosis.
  • Targeting Bcl-xL or the mitochondrial pathway may overcome this novel MDR mechanism.

More Related Videos

Strategies for Tracking Anastasis, A Cell Survival Phenomenon that Reverses Apoptosis12:55

Strategies for Tracking Anastasis, A Cell Survival Phenomenon that Reverses Apoptosis

Published on: February 16, 2015

Knockdown of FAM83A to Verify Its Role in Cervical Cancer Cell Growth and Cisplatin Sensitivity04:20

Knockdown of FAM83A to Verify Its Role in Cervical Cancer Cell Growth and Cisplatin Sensitivity

Published on: February 9, 2024

Related Concept Videos

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...
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...
Caspases01:24

Caspases

Caspase, a family of cysteine proteases, serve as effectors in apoptosis. The ced3 gene in C.elegans was first identified to be involved in apoptosis. This gene encodes the ced-3 caspase that is similar to the interleukin-1-beta converting enzyme or ICE in mammals. In addition to apoptosis, caspases also function in the inflammatory response. Inflammatory caspases are essential in activating pro-inflammatory cytokines that recruit immune cells and block the replication of pathogens inside cells.
The Extrinsic Apoptotic Pathway01:17

The Extrinsic Apoptotic Pathway

The extrinsic apoptotic pathway is initiated when extracellular death-inducing signals, such as specific cytokines, activate the death receptors expressed on the cell surface. The immune cells involved in this pathway are natural killer cells (NK cells) and cytotoxic T-lymphocytes. NK cells are critical in innate immune response, while cytotoxic T-lymphocytes are associated with adaptive immune response. These cells recognize specific receptors expressed on the altered cells and activate...
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...
Cellular Injury V: Apoptosis and Autophagy01:22

Cellular Injury V: Apoptosis and Autophagy

Cells respond to damage and stress through highly coordinated processes that decide whether they survive or undergo controlled self-destruction. Two major pathways involved in this regulation are apoptosis, a type of programmed cell death, and autophagy, a survival mechanism that helps cells adapt to adverse conditions.ApoptosisApoptosis removes aged or injured cells to maintain tissue balance. During this process, the cell shrinks, chromatin condenses and fragments, and membrane-bound...