Bibliographic Details
| Title: |
Lonidamine Induced Selective Acidification and De-Energization of Prostate Cancer Xenografts: Enhanced Tumor Response to Radiation Therapy. |
| Authors: |
Orlovskiy, Stepan, Gupta, Pradeep Kumar, Roman, Jeffrey, Arias-Mendoza, Fernando, Nelson, David S., Koch, Cameron J., Narayan, Vivek, Putt, Mary E., Nath, Kavindra |
| Source: |
Cancers; Apr2024, Vol. 16 Issue 7, p1384, 16p |
| Subject Terms: |
HETEROCYCLIC compounds, AUTOANALYZERS, NUCLEAR magnetic resonance spectroscopy, RESEARCH funding, PROSTATE tumors, XENOGRAFTS, DESCRIPTIVE statistics, CELL lines, MOLECULAR structure, RADIATION doses, ADVERSE health care events, ACIDOSIS |
| Abstract: |
Simple Summary: Early prostate cancer treatment with radiation therapy is effective but involves substantial harmful side effects throughout therapy. This study explores the use of the metabolic modulator lonidamine (LND) to sensitize prostate cancer cells to radiation therapy. 1H and 31P magnetic resonance spectroscopy (MRS) were used to non-invasively monitor metabolic changes associated with LND treatment in human prostate cancer tumors implanted in athymic nude mice. The in vivo MRS results were substantiated using classic biochemistry methods by gathering in vitro data from isolated human prostate cancer cell lines. A radiation growth delay experiment performed in xenografted mice combining LND and radiation therapy showed that LND-modified prostate cancer metabolism and significantly increased the efficacy of radiation therapy. These findings indicate that less radiation may be required with LND, reducing side effects, and potentially improving patient management in the clinic. Prostate cancer is a multi-focal disease that can be treated using surgery, radiation, androgen deprivation, and chemotherapy, depending on its presentation. Standard dose-escalated radiation therapy (RT) in the range of 70–80 Gray (GY) is a standard treatment option for prostate cancer. It could be used at different phases of the disease (e.g., as the only primary treatment when the cancer is confined to the prostate gland, combined with other therapies, or as an adjuvant treatment after surgery). Unfortunately, RT for prostate cancer is associated with gastro-intestinal and genitourinary toxicity. We have previously reported that the metabolic modulator lonidamine (LND) produces cancer sensitization through tumor acidification and de-energization in diverse neoplasms. We hypothesized that LND could allow lower RT doses by producing the same effect in prostate cancer, thus reducing the detrimental side effects associated with RT. Using the Seahorse XFe96 and YSI 2300 Stat Plus analyzers, we corroborated the expected LND-induced intracellular acidification and de-energization of isolated human prostate cancer cells using the PC3 cell line. These results were substantiated by non-invasive 31P magnetic resonance spectroscopy (MRS), studying PC3 prostate cancer xenografts treated with LND (100 mg/kg, i.p.). In addition, we found that LND significantly increased tumor lactate levels in the xenografts using 1H MRS non-invasively. Subsequently, LND was combined with radiation therapy in a growth delay experiment, where we found that 150 µM LND followed by 4 GY RT produced a significant growth delay in PC3 prostate cancer xenografts, compared to either control, LND, or RT alone. We conclude that the metabolic modulator LND radio-sensitizes experimental prostate cancer models, allowing the use of lower radiation doses and diminishing the potential side effects of RT. These results suggest the possible clinical translation of LND as a radio-sensitizer in patients with prostate cancer. [ABSTRACT FROM AUTHOR] |
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| Database: |
Complementary Index |
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