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188Re-HYNIC-trastuzumab enhances the effect of apoptosis induced by trastuzumab in HER2-overexpressing breast cancer cells

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Abstract

Purpose

The development of radioimmunotherapy has provided an impressive alternative approach in improving trastuzumab therapy. However, the mechanisms of trastuzumab and radiation treatment combined to increase therapeutic efficacy are poorly understood. Here, we try to examine the efficacy of cytotoxicity and apoptosis induction for 188Re-HYNIC-trastuzumab in cancer cell lines with various levels of Her2.

Materials and methods

Fluorescence flow cytometry was used to detect the alterations of apoptosis induction after 188Re-HYNIC-trastuzumab treatment in two breast cancer cell lines with different levels of HER2 (BT-474 and MCF-7) and a colorectal carcinoma cell line (HT-29) for control.

Results

Our results indicated that 188Re-HYNIC-trastuzumab led to cell death of breast cancer cells specifically in HER2 level-dependent and radioactivity dose-dependent fashions. In BT-474 cells, 370 kBq/ml of 188Re-HYNIC-trastuzumab enhanced the cytotoxicity to a level nearly 100-fold that of trastuzumab-alone treatment. The results also revealed that the mitochondria-dependent pathway attenuated irradiation-induced apoptosis in HER2-expressing breast cancer cells after 188Re-HYNIC-trastuzumab treatment. In contrast, only after 48 h of 188Re-HYNIC-trastuzumab treatment, BT-474 cells exhibited typical apoptotic changes, including exposure of phospholipid phosphatidylserine on the cell surface, or fragmented DNA formation, in a radioactivity dose-dependent manner.

Conclusion

Briefly, our study demonstrates that 188Re-labeled HYNIC-trastuzumab not only enhances cell death in a radioactivity dose-dependent fashion, but may also prolong the effects of apoptosis involved with the mitochondria-dependent pathway in HER2-overexpressing breast cancer cells. It is possible that the 188Re-HYNIC-trastuzumab treatment induced a second round of apoptosis to prolong the effects of cell kill in these cancer cells. These data revealed that 188Re-HYNIC-trastuzumab has the potential for use as a therapeutic radiopharmaceutical agent in HER2-overexpressing breast cancer cell treatment.

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Authors and Affiliations

  1. Isotope Application Division, Institute of Nuclear Energy Research, P.O. BOX 3-27, No. 1000, Wenhua Rd., Jiaan Village, Longtan Township, Taoyuan, 32546, Taiwan

    Tsai-Yueh Luo, Ping-Fang Chiang, Chung-Hsin Yeh & Wuu-Jyh Lin

  2. Institute of Radiological Science, Central Taiwan University of Science and Technology, Taichung, Taiwan

    Tsai-Yueh Luo

  3. Department of Parasitology, College of Medicine, Taipei Medical University, 250 Wuxing St, Taipei, 11031, Taiwan

    Po-Ching Cheng & Ting-Wu Chuang

  4. Center for International Tropical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan

    Po-Ching Cheng & Ting-Wu Chuang

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  1. Tsai-Yueh Luo
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  2. Po-Ching Cheng
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Correspondence to Tsai-Yueh Luo or Po-Ching Cheng.

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Luo, TY., Cheng, PC., Chiang, PF. et al. 188Re-HYNIC-trastuzumab enhances the effect of apoptosis induced by trastuzumab in HER2-overexpressing breast cancer cells. Ann Nucl Med 29, 52–62 (2015). https://doi.org/10.1007/s12149-014-0908-8

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  • DOI: https://doi.org/10.1007/s12149-014-0908-8

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