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Published on: June 18, 2013
Induction of targeted necrosis with HER2-targeted platinum(iv) anticancer prodrugs
Daniel Yuan Qiang Wong1, Jun Han Lim1, Wee Han Ang1,2
1Department of Chemistry , National University of Singapore , Singapore 117543 , Singapore . Email: chmawh@nus.edu.sg ; Tel: +65 6516 5131.
Abstract:
It is well-recognized that the failure of many chemotherapeutics arises due to an inability to induce apoptosis. Most cancers acquire a myriad of pro-survival adaptations, and the vast heterogeneity and accumulation of multiple often unrelated anti-apoptotic signaling pathways have been a major stumbling block towards the development of conventional chemotherapeutics, which can overcome drug resistance. We have developed highly potent and selective HER2-targeted Pt(iv) prodrugs bearing anti-HER2/neu peptides that induce targeted necrosis as a novel strategy to circumvent apoptosis-resistance. These Pt(iv)-peptide conjugates exhibit a unique biphasic mode of cytotoxicity comprising rapid killing of cancer cells via necrosis in the first phase followed by an extended and gradual phase of delayed cell death. We demonstrate that these Pt(iv)-peptide prodrugs are more potent than their Pt(ii) congeners in direct cell-killing and exhibit comparable long-term inhibition of proliferative capacity and with greater selectivity against HER2-positive cancer cells.
Insights
New platinum(IV) (Pt(iv)) prodrugs target HER2-positive cancer cells, inducing targeted necrosis to overcome apoptosis resistance. These novel agents show enhanced potency and selectivity, offering a promising strategy against drug-resistant cancers.
Area of Science:
- Biochemistry
- Oncology
- Materials Science
Background:
- Chemotherapeutic failure is often linked to cancer cells' resistance to apoptosis.
- Multiple pro-survival pathways in heterogeneous cancers present a significant challenge for conventional treatments.
- Drug resistance in cancer necessitates novel therapeutic strategies beyond apoptosis induction.
Purpose of the Study:
- To develop potent and selective HER2-targeted platinum(IV) (Pt(iv)) prodrugs.
- To utilize targeted necrosis as a strategy to circumvent apoptosis resistance in cancer.
- To evaluate the efficacy and selectivity of Pt(iv)-peptide conjugates against HER2-positive cancer cells.
Main Methods:
- Synthesis of HER2-targeted Pt(iv) prodrugs conjugated with anti-HER2/neu peptides.
- Assessment of cytotoxicity and mode of cell death (apoptosis vs. necrosis).
- Comparison of Pt(iv) prodrugs with their Pt(ii) counterparts in HER2-positive cancer models.
Main Results:
- Pt(iv)-peptide conjugates successfully induced targeted necrosis in cancer cells.
- The prodrugs exhibited a biphasic cytotoxicity: rapid necrosis followed by delayed cell death.
- Pt(iv) prodrugs demonstrated greater potency and selectivity than Pt(ii) agents against HER2-positive cancer cells.
Conclusions:
- HER2-targeted Pt(iv) prodrugs offer a novel approach to overcome apoptosis resistance.
- Targeted necrosis induction by Pt(iv)-peptide conjugates is an effective strategy for cancer therapy.
- These prodrugs present a promising therapeutic option with enhanced efficacy and selectivity for HER2-positive cancers.
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