Targeting entry into mitochondria for increased anticancer efficacy of BCL-XL-selective inhibitors in lung cancer
Liangping Li1, Pingping Li1, Huanhuan Song1
1State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Ministry of Science and Technology of China, Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin 541004, China.
Abstract:
The BCL-XL-selective inhibitors exhibit potential clinical application value when combined with chemotherapeutic drugs for the treatment of solid tumors. However, their efficacy in these settings is still low when treated with BCL-XL inhibitors alone in solid tumors. The mechanism responsible for the poor efficacy remains unclear. We show here that unable to interact with target of BCL-XL-selective inhibitors caused by invalid entry into mitochondria is essential for their inefficacy in solid tumors. We demonstrated in non-small-cell lung cancer (NSCLC) cells that the instability of A-1155463 in cells as well as invalid entry into mitochondria of A-1331852, two BCL-XL-selective inhibitors, accounted for their off-target problems. Furthermore, we found that a mitochondria-targeted, non-toxic small molecule NA-2a improved the on-target effect of A-1331852 to enhance its apoptotic regulatory activity, thereby increasing its anticancer activity in NSCLC. Our results indicated that NA-2a was selectively enriched in mitochondria transported by organic-anion-transporting polypeptide (OATP) transporters, which altered the permeability of the mitochondrial membrane, thereby promoting the entrance of A-1331852 to mitochondria and enhancing its disruption of the BIM-BCL-XL complex, which finally led to the increased anticancer activity in vitro and in vivo. Collectively, our data provided overwhelming evidence that the combination of NA-2a and A-1331852 could be used as a promising synergistic therapeutic agent in NSCLC therapy.
Insights
Mitochondria-targeted NA-2a enhances BCL-XL inhibitor efficacy in non-small-cell lung cancer (NSCLC). This combination improves drug delivery and disrupts cancer cell survival, offering a promising new therapy for solid tumors.
Area of Science:
- Molecular oncology
- Cancer therapeutics
- Drug delivery systems
Background:
- BCL-XL-selective inhibitors show promise for solid tumors but have low efficacy alone.
- The underlying mechanisms for poor efficacy of BCL-XL inhibitors in solid tumors are not fully understood.
- Mitochondrial dysfunction and drug entry are critical factors in inhibitor performance.
Purpose of the Study:
- To elucidate the mechanism behind the poor efficacy of BCL-XL-selective inhibitors in solid tumors.
- To investigate the role of mitochondrial entry and drug stability in non-small-cell lung cancer (NSCLC).
- To evaluate the potential of a mitochondria-targeted small molecule (NA-2a) to enhance the efficacy of BCL-XL inhibitors.
Main Methods:
- Assessment of BCL-XL inhibitor stability and mitochondrial entry in NSCLC cells.
- Utilized a mitochondria-targeted small molecule, NA-2a, to improve drug delivery and on-target effects.
- Investigated the role of organic-anion-transporting polypeptide (OATP) transporters in NA-2a mitochondrial uptake.
- Evaluated the synergistic anticancer activity of NA-2a and A-1331852 in vitro and in vivo.
Main Results:
- Instability and poor mitochondrial entry of BCL-XL inhibitors (A-1155463, A-1331852) contribute to their limited efficacy in NSCLC.
- NA-2a, a mitochondria-targeted molecule, enhances the entry of A-1331852 into mitochondria via OATP transporters.
- The combination of NA-2a and A-1331852 significantly increased apoptotic activity and anticancer effects in NSCLC models.
Conclusions:
- Mitochondrial targeting is crucial for overcoming the inefficacy of BCL-XL-selective inhibitors in solid tumors.
- NA-2a acts synergistically with A-1331852 by improving mitochondrial drug accumulation and BIM-BCL-XL complex disruption.
- The combination of NA-2a and A-1331852 represents a promising therapeutic strategy for NSCLC treatment.
Related Concept Videos
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...
01:46Electron Transport Chain: Complex I and II
ROS generation is regulated and maintained at moderate levels necessary...
02:50Combination Therapies and Personalized Medicine
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...
01:31The Intrinsic Apoptotic Pathway