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Updated: Feb 12, 2026
Studying Triple Negative Breast Cancer Using Orthotopic Breast Cancer Model
Published on: March 20, 2020
A cyclometalated iridium(III) complex induces paraptotic cell death via mitochondrial dysfunction and ER stress in
Houmin Lin1,2,3, Jianhua Wei1, Wenmin Yao1,2,3
1Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, The First Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China.
Background:
Given the lack of targeted therapies and frequent resistance to apoptosis-based treatments, triple-negative breast cancer (TNBC) remains a major clinical challenge. Exploring non-apoptotic cell death mechanisms may offer new therapeutic avenues to circumvent drug resistance in TNBC.
Methods:
The anticancer activity of a novel cyclometalated iridium (III) compound, CIr2, was evaluated using cytotoxicity, clonogenic, and migration assays in multiple breast cancer cell lines. Mechanistic investigations included analyses of mitochondrial dysfunction, reactive oxygen species (ROS) production, ATP depletion, endoplasmic reticulum (ER) stress, and MAPK signaling. Transcriptomic profiling (RNA-seq), ultrastructural and morphological analyses, as well as pharmacological inhibitor studies targeting distinct cell death pathways, were performed to elucidate the mode of cell death induced by CIr2. The in vivo antitumor efficacy and safety of CIr2 were further assessed using a TNBC xenograft mouse model.
Results:
CIr2 selectively inhibited the proliferation and migration of TNBC cells while exerting minimal cytotoxic effects on normal breast epithelial cells. CIr2 preferentially accumulated in mitochondria, leading to mitochondrial membrane potential collapse, excessive ROS production, and profound ATP depletion. Transcriptomic profiling and morphological analyses revealed pronounced ER stress, MAPK pathway activation, and paraptosis-associated ultrastructural alterations, including mitochondrial swelling and extensive cytoplasmic vacuolization. Pharmacological inhibition of apoptosis, necroptosis, ferroptosis, autophagy, ER stress, or p38 MAPK signaling failed to rescue CIr2-induced cytotoxicity, whereas ROS scavenging effectively reversed these effects, confirming a mitochondrial dysfunction and ROS-driven paraptotic mode of cell death. In vivo, CIr2 markedly suppressed TNBC xenograft tumor growth with minimal systemic toxicity.
Conclusion:
CIr2 induces paraptosis through mitochondrial dysfunction and ER stress, offering a potential therapeutic strategy to overcome apoptosis resistance in TNBC. These findings provide a new mechanistic insight into iridium-based paraptosis induction.
Insights
A novel iridium compound, CIr2, effectively targets triple-negative breast cancer (TNBC) by inducing paraptosis, a non-apoptotic cell death. This offers a promising new strategy to overcome treatment resistance in TNBC patients.
Area of Science:
- Biochemistry
- Cell Biology
- Oncology
Background:
- Triple-negative breast cancer (TNBC) presents a significant clinical challenge due to limited targeted therapies and frequent resistance to apoptosis-based treatments.
- Exploring alternative cell death mechanisms is crucial for developing novel therapeutic strategies against TNBC.
- Investigating novel compounds that can circumvent existing drug resistance pathways is a key area of research.
Purpose of the Study:
- To evaluate the anticancer activity of a novel cyclometalated iridium (III) compound, CIr2, against breast cancer cell lines, particularly TNBC.
- To elucidate the mechanism of cell death induced by CIr2, focusing on non-apoptotic pathways.
- To assess the in vivo efficacy and safety of CIr2 in a TNBC xenograft model.
Main Methods:
- Cytotoxicity, clonogenic, and migration assays were performed on multiple breast cancer cell lines.
- Mechanistic studies involved analyzing mitochondrial dysfunction, ROS production, ATP depletion, ER stress, and MAPK signaling.
- Transcriptomic profiling (RNA-seq), ultrastructural analyses, and pharmacological inhibitor studies were conducted to determine the mode of cell death.
Main Results:
- CIr2 selectively inhibited TNBC cell proliferation and migration with minimal toxicity to normal cells.
- CIr2 induced mitochondrial dysfunction, ROS production, ATP depletion, ER stress, and paraptosis-associated ultrastructural changes.
- Cell death was confirmed to be ROS-driven paraptosis, independent of apoptosis, necroptosis, ferroptosis, or autophagy pathways.
Conclusions:
- CIr2 induces paraptosis via mitochondrial dysfunction and ER stress, representing a potential therapeutic strategy for apoptosis-resistant TNBC.
- These findings offer new insights into iridium-based compounds as inducers of paraptosis.
- CIr2 demonstrated significant in vivo antitumor efficacy in a TNBC xenograft model with minimal systemic toxicity.
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