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Degradation of HER2 receptor through hypericin-mediated photodynamic therapy
Ján Koval1, Jaromír Mikes, Rastislav Jendzelovský
1Faculty of Sciences, Institute of Biology and Ecology, P. J. Safárik University in Kosice, Kosice, Slovakia.
Abstract:
Current treatment of breast cancer is often affected by resistance to therapeutics, for which the human epidermal growth factor receptor 2 (HER2) may be responsible. Here, we report for the first time the use of hypericin-mediated photodynamic therapy (HY-PDT) in combination with a selective HER2 inhibitor (AG 825) on SKBR-3, a HER2 overexpressing human breast adenocarcinoma cell line. The results demonstrate that HY-PDT is able to degrade HER2 with an impact on its signaling cascade. Combination with AG 825 resulted in increased apoptosis induction, total degradation of HER2 and inhibition of colony formation. Downregulation of HSP90, Mcl-1, Bcl-xL and upregulation of Bax was also observed. This knowledge provides the basis for the possible application of HY-PDT in preclinical and clinical models of breast cancer treatment.
Insights
Hypericin-mediated photodynamic therapy (HY-PDT) combined with a HER2 inhibitor (AG 825) effectively degrades HER2, increases breast cancer cell apoptosis, and inhibits colony formation in preclinical models.
Area of Science:
- Oncology
- Biochemistry
- Photomedicine
Background:
- Breast cancer treatment faces challenges due to therapeutic resistance, potentially linked to human epidermal growth factor receptor 2 (HER2).
- Targeting HER2 is a key strategy in managing HER2-overexpressing breast cancers.
Purpose of the Study:
- To investigate the efficacy of hypericin-mediated photodynamic therapy (HY-PDT) alone and in combination with a selective HER2 inhibitor (AG 825).
- To evaluate the effects of this combination therapy on HER2 degradation and downstream signaling in HER2-positive breast cancer cells.
Main Methods:
- Utilized SKBR-3 human breast adenocarcinoma cells, which overexpress HER2.
- Applied HY-PDT and the selective HER2 inhibitor AG 825, both individually and in combination.
- Assessed HER2 degradation, apoptosis induction, colony formation, and expression of key proteins (HSP90, Mcl-1, Bcl-xL, Bax).
Main Results:
- HY-PDT demonstrated the ability to degrade HER2 and impact its signaling cascade.
- The combination of HY-PDT and AG 825 led to enhanced apoptosis induction and complete HER2 degradation.
- Combined treatment significantly inhibited colony formation and modulated the expression of apoptosis-related proteins (downregulation of HSP90, Mcl-1, Bcl-xL; upregulation of Bax).
Conclusions:
- The combination of HY-PDT and AG 825 presents a promising therapeutic strategy for HER2-overexpressing breast cancer.
- This approach effectively targets HER2, induces apoptosis, and inhibits tumor cell proliferation.
- Findings support further investigation of HY-PDT and HER2 inhibition in preclinical and clinical breast cancer settings.
