One of the ways by which prostate cancer cells survive or become resistant to conventional therapies is through the ability to reprogram their metabolic pathways. Thus, justifying the need for studies to elucidate the efficacy of metabolic inhibitors in prostate cancer intervention. The purpose of this study was to investigate the synergistic effects of two metabolic pathway inhibitors - 3-bromopyruvate (3-BrPA) and genistein - on androgen sensitive (LNCaP) and androgen insensitive (DU145) spheroid prostate cancer cells separately primed or irradiated with very low doses of x-ray radiation (VLDR) and low frequency weak magnetic field radiation (MFR).

Methods: Both PCa cells were cultured until they form spheroids and then irradiated with either VLDR (20mGy/hr) or MFR (10mT; 50Hz/hr) in separate groups. Cells were seeded and treated with varying doses of 3-BrPA and genistein in single or combination regimen. Cell viability, metabolic activity and cytotoxicity or LDH release levels were measured using MTT, Alamar blue and LDH assays respectively. NBT assay was used to determine treatment-induced ROS levels. mitochondrial membrane potential was determined by Rh123 and ethidium bromide fluorescent staining. Modes of Cell death were determined by fluorescent staining with acridine orange and ethidium bromide dyes, and by morphological identification of apoptotic and autophagic PCa cells. CompuSyn program was used to determine the time- and dose-dependent synergism between combination regimens.

Results: Our results show that VLDR and weak MFR moderately inhibit cell proliferation in both PCa cell lines. However, LNCaP PCa cells were found to be more responsive to both VLDR or weak MFR compared to DU-145 PCa cells. Both VLDR and MFR suppresses ATP generation and increases ROS generation time-dependently in both cell lines. The most common cell death event found in MFR-exposed cells was a mixture of mitotic catastrophe and autophagy, while autophagic and slight apoptotic responses were observed in VLDR-exposed cells. 3-BrPA triggers more autophagic response in irradiated DU145 cells compared more apoptotic response in LNCaP cells. In contrast, genistein induced cell growth inhibition in both cell lines, but more effect was observed in LNCaP cells with dose-dependent apoptotic response. Combination of 3-BrPA and genistein forced PCa cells to undergo reprogrammed cell death, decreased the mitochondrial membrane potential and LDH levels significantly in a dose and time-dependently.

Conclusion: The combination treatments show synergistic and significant inhibition of the glycolytic and mitochondrial metabolic pathways resulting in induction of apoptosis in radiochemosensitized PCa cells. Priming of cells with VLDR or MFR also enhanced the therapeutic effects of both metabolic inhibitors. Hence, reinforcing the potential benefit of metabolic inhibitors in prostate cancer treatment.

Note: This abstract was not presented at the meeting.

Citation Format: Saheed O. Oseni, Rolando Branly, Mirjana Pavlovic, James Kumi-Diaka. Synergistic effects of metabolic inhibitors on radiochemosensitized spheroid prostate cancer cells [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 5422. doi:10.1158/1538-7445.AM2017-5422