Related Experiment Video
Updated: Jul 11, 2025
Establishing Cell Lines Overexpressing DR3 to Assess the Apoptotic Response to Anti-mitotic Therapeutics
Published on: January 11, 2019
Chimeric Small Molecules for Detouring Drugs into Mitochondria to Engender Apoptosis in Cancer Cells
Tripti Mishra1, Abhinav Gautam1, Jaypalsing Ingle1
1Department of Chemistry, Indian Institute of Technology Gandhinagar, Palaj, Gandhinagar, Gujarat, 382355, India.
Abstract:
Mitochondrion has appeared as one of the important targets for anti-cancer therapy. Subsequently, small molecule anti-cancer drugs are directed to the mitochondria for improved therapeutic efficacy. However, simultaneous imaging and impairing mitochondria by a single probe remained a major challenge. To address this, herein Chimeric Small Molecules (CSMs) encompassing drugs, fluorophore and mitochondria homing moiety were designed and synthesized through a concise strategy. Screening of the CSMs in a panel of cancer cell lines (HeLa, MCF7, A549, and HCT-116) revealed that one of the CSMs comprising Indomethacin V exhibited remarkable cervical cancer cell (HeLa) killing (IC50 =0.97 μM). This lead CSM homed into the mitochondria of HeLa cells within 1 h followed by mitochondrial damage and reactive oxygen species (ROS) generation. This novel Indomethacin V-based CSM-mediated mitochondrial damage induced programmed cell death (apoptosis). We anticipate these CSMs can be used as tools to understand the drug effects in organelle chemical biology in diseased states.
Insights
Researchers developed novel Chimeric Small Molecules (CSMs) for simultaneous cancer cell imaging and mitochondrial impairment. A lead Indomethacin V-based CSM effectively killed cervical cancer cells by targeting mitochondria, inducing damage and apoptosis.
Area of Science:
- Mitochondrial targeted therapy
- Organelle chemical biology
- Cancer drug development
Background:
- Mitochondria are crucial targets for anti-cancer drug development.
- Directing small molecule drugs to mitochondria enhances therapeutic efficacy.
- Simultaneously imaging and impairing mitochondria with a single probe presents a challenge.
Purpose of the Study:
- To design and synthesize Chimeric Small Molecules (CSMs) for simultaneous mitochondrial imaging and impairment.
- To evaluate the anti-cancer efficacy of synthesized CSMs in various cancer cell lines.
- To investigate the mechanism of action of a lead CSM in cervical cancer cells.
Main Methods:
- Design and synthesis of CSMs incorporating drugs, fluorophores, and mitochondria-homing moieties.
- Screening of CSMs in HeLa, MCF7, A549, and HCT-116 cancer cell lines.
- Mitochondrial localization, damage, reactive oxygen species (ROS) generation, and apoptosis induction assays.
Main Results:
- A novel Indomethacin V-based CSM demonstrated significant cervical cancer cell (HeLa) killing with an IC50 of 0.97 μM.
- The lead CSM rapidly localized to HeLa cell mitochondria within 1 hour.
- Mitochondrial damage, ROS generation, and apoptosis were induced by the Indomethacin V-based CSM.
Conclusions:
- CSMs offer a promising strategy for simultaneous mitochondrial imaging and therapeutic intervention in cancer.
- The Indomethacin V-based CSM effectively induces apoptosis in cervical cancer cells via mitochondrial pathways.
- These CSMs can serve as valuable tools for studying drug effects in organelle chemical biology in disease states.
More Related Videos
19:44Enhancement 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
07:42Activation of Apoptosis by Cytoplasmic Microinjection of Cytochrome c
Published on: June 29, 2011
Related Concept Videos
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...
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...
01:46Electron Transport Chain: Complex I and II
ROS generation is regulated and maintained at moderate levels necessary...
01:39Mitochondrial Precursor Proteins
Most of the mitochondrial...
01:19Translocation of Proteins into the Mitochondria
Sorting of outer membrane proteins:
Mitochondrial outer membrane proteins are of two types: the transmembrane, beta-barrel porins, and the membrane-anchored, alpha-helical proteins. Beta-barrel porin precursors are translocated by the TOM complex and inserted into the outer mitochondrial membrane by the SAM complex. In contrast,...
01:26Targets for Drug Action: Overview
Receptors are either membrane-spanning or intracellular proteins, which upon binding a ligand, get activated and transmit the signal downstream to elicit a response. Drugs bind receptors, either mimicking the action of endogenous ligands or blocking the receptor activity to bring about a modified response. Nearly 35% of approved drugs target the G...