Therapeutic Potential of Metal-Based and PARP Inhibitor Chemotherapy for BRCA1-Associated Triple-Negative Breast Cancer
Abstract
1. Introduction
2. Role of BRCA1 in BRCA1-Associated Triple-Negative Breast Cancer
3. Platinum-Based Chemotherapy for BRCA1-Associated Triple-Negative Breast Cancer
4. PARP Inhibitors for BRCA1-Associated Triple-Negative Breast Cancer
5. Cellular Resistance to Platinum Drugs
5.1. Decreased Drug Accumulation in Cisplatin Resistance
5.2. Increased Binding to Intracellular Thiol Molecules
5.3. Increased DNA Repair
5.4. Epigenetics in Resistance to Cisplatin
6. Cellular Resistance to PARP Inhibitors
6.1. Reverse Mutation
6.2. Restoration of Replication Fork Stability
6.3. Dysregulation Within Molecular Signaling Pathways
6.4. Enhanced Drug Efflux
7. Ruthenium-Based Chemotherapy for BRCA1-Associated Triple-Negative Breast Cancer
8. Synergistic Effects of Olaparib in Combination with Platinum/Ruthenium-Based Anticancer Agents in BRCA1-Associated Triple-Negative Breast Cancers
9. Future Perspectives
Funding
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Chemotherapy | TNBC (n) | Setting | Outcomes | References |
---|---|---|---|---|
Cisplatin | 86 | Metastatic | RR 37% | [55] |
Olaparib | 27 | Metastatic | pCR 41% | [56] |
Cisplatin/veliparib | 162 | Neoadjuvant | pCR 74% | [57] |
Cisplatin/docetaxel | 27 | Metastatic | ORR 59% | [58] |
Carboplatin/docetaxel | 28 | Neoadjuvant | pCR 86% | [59] |
Carboplatin/veliparib | 634 | Neoadjuvant | pCR 47% | [60] |
Carboplatin/veliparib | 107 | Neoadjuvant | pCR 61% | [61] |
Gemcitabine/carboplatin/iniparib | 258 | Metastatic | ORR 34% | [62] |
Paclitaxel/carboplatin | 24 | Neoadjuvant | pCR 33% | [63] |
Paclitaxel/doxorubicin/cyclophosphamide/carboplatin | 60 | Neoadjuvant | pCR 51% | [64] |
Eribulin/carboplatin | 22 | Neoadjuvant | pCR 40% | [26] |
Paclitaxel/carboplatin/olaparib | 559 | Neoadjuvant | pCR 51% | [65] |
Mitomycin C/vinblastine/cisplatin | 34 | Metastatic | ORR 41% | [66] |
Gemcitabine /carboplatin/iniparib | 80 | Neoadjuvant | ORR 36% | [67] |
Ruthenium Complexes | Phase/ Status | Mechanism of Action/Clinical Challenges | Ref. |
---|---|---|---|
NAMI-A | Phase II |
| [177,178] |
KP-1019 | Phase I |
| [177,178,179] |
KP-1339 | Phase I |
| [177,178] |
TLD1433 | Phase Ib |
| [177,178,180] |
BOLD-100 | Phase I |
| [177,178,180] |
RM175 | Preclinical |
| [177] |
RAED-C | Preclinical |
| [177,181,182,183] |
RAPTA-C | Preclinical |
| [177,181,182,183,184] |
Class | Primary Mechanism | Toxicity | Efficacy |
---|---|---|---|
Platinum complexes | Platinum complexes exert cytotoxicity by forming DNA crosslinks that disrupt replication and transcription, leading to the accumulation of unrepaired DNA lesions, cell cycle arrest, and apoptosis in TNBC [203] |
|
|
PARP inhibitors | PARP inhibitors indicate antitumor effects in TNBC by blocking the repair of single-strand DNA breaks (SSBs), leading to the accumulation of double-strand breaks (DSBs) during replication. In BRCA1/2 mutant or HR-deficient TNBC, these lesions cannot be effectively repaired, resulting in synthetic lethality [205] |
|
|
Ruthenium complexes | Ru(III) complexes are involved in TNBC by accumulating in mitochondria, causing mitochondrial dysfunction, ROS generation, and membrane depolarization, which leads to DNA damage and cell death. Additionally, ruthenium inhibits the protein expression of macrophage colony-stimulating factor (M-CSF), which is relevant to the PI3K/AKT/mTOR pathway, thereby reducing migration, invasion, and angiogenesis of cancer cells [181] |
|
|
Class | Mechanism | Advantages | Limitations | Clinical Status |
---|---|---|---|---|
Platinum drugs | The cytotoxicity of platinum complexes arises from the covalent binding of platinum atoms to the N7 position of purine bases in DNA, forming platinum adducts that generate intrastrand and interstrand crosslinks. This blocks replication and transcription, inhibits DNA synthesis, induces cell cycle arrest, and ultimately triggers apoptosis in cancer cells [207] | Widely used for the treatment of cancer
| High toxicity
|
|
PARP inhibitors | PARP inhibitors induce synthetic lethality by inhibiting PARP1/2 catalytic activity, preventing the repair of single-strand DNA breaks (SSBs) and leading to their accumulation. This results in the formation of double-strand breaks (DSBs). In HR-deficient tumors (e.g., BRCA1/2 mutants), DSBs cannot be efficiently repaired, ultimately leading to cell death (apoptosis) [95] |
[214] | ||
Ruthenium complexes | Ru(II) complexes inhibit tumor growth and metastasis by entering the nucleus, binding to DNA, inducing DNA damage, and causing cell cycle arrest. Additionally, ruthenium can localize to mitochondria, leading to mitochondrial dysfunction, increased ROS generation, and apoptosis of cancer cells [215] |
| Ru(II) complexes are not FDA-approved and are still under clinical evaluation in humans
|
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Ratanaphan, A. Therapeutic Potential of Metal-Based and PARP Inhibitor Chemotherapy for BRCA1-Associated Triple-Negative Breast Cancer. Int. J. Mol. Sci. 2025, 26, 9881. https://doi.org/10.3390/ijms26209881
Ratanaphan A. Therapeutic Potential of Metal-Based and PARP Inhibitor Chemotherapy for BRCA1-Associated Triple-Negative Breast Cancer. International Journal of Molecular Sciences. 2025; 26(20):9881. https://doi.org/10.3390/ijms26209881
Chicago/Turabian StyleRatanaphan, Adisorn. 2025. "Therapeutic Potential of Metal-Based and PARP Inhibitor Chemotherapy for BRCA1-Associated Triple-Negative Breast Cancer" International Journal of Molecular Sciences 26, no. 20: 9881. https://doi.org/10.3390/ijms26209881
APA StyleRatanaphan, A. (2025). Therapeutic Potential of Metal-Based and PARP Inhibitor Chemotherapy for BRCA1-Associated Triple-Negative Breast Cancer. International Journal of Molecular Sciences, 26(20), 9881. https://doi.org/10.3390/ijms26209881