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PAC, a novel curcumin analogue, has anti-breast cancer properties with higher efficiency on ER-negative cells

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Abstract

We have investigated here the anti-breast cancer properties of two novel curcumin analogues, EAC and PAC. Apoptosis was assessed by the annexin V/propidium iodide (PI) assay on different breast cancer and normal cells. Immunoblotting analysis determined the effects of these agents on different apoptotic and oncogenic proteins. Furthermore, flow cytometry and Elispot were utilised to investigate the effects on the cell cycle and the production of cytokines, respectively. Breast cancer tumour xenografts were developed in nude mice. Finally, 18F-radiolabeled PAC and curcumin were produced to study their bioavailability and tissue biodistribution in mice. PAC is five times more efficient than curcumin and EAC in inducing apoptosis, mainly via the internal mitochondrial route. This effect was 10-fold higher against ER-negative as compared to ER-positive cells, and ectopic expression of ERα rendered ER-negative breast cancer cells more resistant to PAC. In addition, PAC delayed the cell cycle at G2/M phase with a stronger effect on ER-negative cells. Moreover, PAC exhibited strong capacity as an immuno-inducer through reducing the secretion of the two major Th2 cytokines IL-4 and IL-10. Importantly, PAC significantly reduced tumour size, and triggered apoptosis in vivo. Furthermore, PAC inhibited survivin, NF-kB and its downstream effectors cyclin D1 and Bcl-2, and strongly up-regulated p21WAF1 both in vitro and in tumours. Besides, PAC exhibited higher stability in blood and greater biodistribution and bioavailability than curcumin in mice. These results indicate that PAC could constitute a powerful, yet not toxic, new chemotherapeutic agent against ER-negative breast tumours.

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Acknowledgments

We are grateful to Ben Ho Park for providing us with the ER-expressing pIRESneo3 plasmid. We would like also to thank Dr. Ra’afat El-Sayed, Falah Al-Mohanna and Jonathan Caijas for their help with animal studies. We are also thankful to Dr. Bedri Karakas and Dr. Abde Abukhdeir for their help and fruitful discussions. This work was performed under the RAC proposal # 2050039 and was supported by King Abdelaziz city of Sciences and technology (KACST proposal # 08-MED476-20).

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Author notes

  1. Khairia M. Youssef

    Present address: Future University, New Cairo City, Main City Center, Cairo, Egypt

Authors and Affiliations

  1. Department of Biological and Medical Research, King Faisal Specialist Hospital and Research Center, MBC # 03, PO Box 3354, Riyadh, 11211, KSA

    Ensaf M. Al-Hujaily, Ibtehaj Al-Sharif & Abdelilah Aboussekhra

  2. Histocompatibility and Immunogenetics Research Unit, Stem Cell Therapy Program, King Faisal Specialist Hospital and Research Center, MBC # 03, PO Box 3354, Riyadh, 11211, KSA

    Ameera Gaafar Mohamed & Khaled Al-Hussein

  3. King Saud University, PO Box 2454, Riyadh, 11451, KSA

    Khairia M. Youssef & Amal Al-Haza’a

  4. Stem Cell Therapy Program, King Faisal Specialist Hospital and Research Center, MBC # 03, PO Box 3354, Riyadh, 11211, KSA

    Pulicat S. Manogaran

  5. Department of Cyclotron and Radiopharmaceuticals, King Faisal Specialist Hospital and Research Center, MBC # 03, PO Box 3354, Riyadh, 11211, KSA

    Basem Al-Otaibi & Ibrahim Al-Jammaz

  6. College of Medicine, Al-Faisal University, P.O. Box 50927, Riyadh, 11533, KSA

    Abdelilah Aboussekhra

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  1. Ensaf M. Al-Hujaily
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Correspondence to Abdelilah Aboussekhra.

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Al-Hujaily, E.M., Mohamed, A.G., Al-Sharif, I. et al. PAC, a novel curcumin analogue, has anti-breast cancer properties with higher efficiency on ER-negative cells. Breast Cancer Res Treat 128, 97–107 (2011). https://doi.org/10.1007/s10549-010-1089-3

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  • DOI: https://doi.org/10.1007/s10549-010-1089-3

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