The substrate selectivity of the isolated dehydratase (DH) domain of a fungal highly-reducing polyketide synthase is closely related to that of mammalian fatty acid synthase.

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Background: Breast cancer is the most common cancer in women in the United Kingdom. The glutathione (GSH) system is a major redox buffering system involved in regulating radioresponse of cancer cells. Overexpression has been shown to cause multidrug and radiation resistance. Its modulation may increase radiosensitivity and improve radiotherapy efficacy. Piperlongumine (PL) can reportedly inhibit GSH system function and reduce proliferation of a variety cancer cells in vitro. The current study investigates novel PL analogues to determine efficacy in triple-negative (TNBC) and luminal breast cancer cell lines, as both single agents and in combination with ionising radiation. Methods: Two novel PL analogues (LH91 and LH92) were used along with the parental drug, PL. Cell proliferation assays were conducted in MDA-MB-231 (TNBC) and T47D (luminal) lines at various drug concentrations and times. At 48hr post treatment, cells were also assessed for clonogenic survival. Clonogenic radiosensitisation was assessed by treating with PL agents or L-buthionine-S, R-sulfoximine (BSO, a well characterised GSH radiosensitiser) for 48hr then irradiation with 0-8Gy X-rays. ROS levels were evaluated using H2DCFDA flow cytometry following IC50 drug treatment alone or with subsequent exposure to 1mM H2O2 for 1hr. Results: PL, LH91 and LH92 inhibited proliferation and decreased clonogenic survival in both lines. From proliferation assays, MDA-MB-231 cells were more sensitive to PL at 48hr (P=0.047) and 72hr (P=0.01) with an IC50 dose of approx. 4μM versus approx. 12μM in T47D’s. There was a significant difference between IC50 doses of LH91 in MDA-MB-231 (5μM) and T47D (12μM) cell lines at 72hr (P=0.006), however this was not observed at 48hr treatment (P=0.178). In contrast, there was no differential sensitivity of LH92 in cell proliferation between the two cell lines at 48 and 72hr. Interestingly, in clonogenic assays, MDA-MB-231’s were more sensitive to LH92 (P=0.01) with an IC50 of 4μM versus 11μM in T47D’s. There were no significant differences in clonogenic survival between each line after treatment with PL or LH91. No radiosensitisation was observed with PL or PL analogues in MDA-MBA-231 however BSO, as a drug comparator, enhanced radiation response with a sensitizer enhancement ratio (SER) of 1.13 at 1% iso-survival. Radiation and drug combinations in T47D cells are ongoing. There were no changes in ROS levels with the drug alone in MDA-MB-231; however, with subsequent exposure of H2O2, there was a 1.7-fold increase in ROS level with LH91 at 48hr (P=0.002). Conclusion: The TNBC cell line is more sensitive to the cytotoxic effect of PL agents (PL and LH91 in cell proliferation and LH92 in clonogenic assays) in comparison to the luminal cell line; however no altered radiosensitisation was observed. The mechanism of such differential sensitivity is yet to be determined. Note: This abstract was not presented at the meeting. Citation Format: Nurul Akmaryanti Abdullah, John Moses, Li Chen Han, Sarah Storr, Aula Ammar, Stewart G. Martin. Differential cytotoxic effects of Piperlongumine analogues and their radiotherapeutic response in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5210. doi:10.1158/1538-7445.AM2017-5210