Antitumor Effects of Zoledronic Acid under Hypoxia

Bisphosphonates are widely used in the clinic for the treatment of osteoporosis, osteogenesis imperfecta, fibrous dysplasia and of various malignancies. In cancer treatment they are mainly used palliatively to reduce loss of bone density as a result of metastasis. In addition, several reports also claim a direct effect on the tumor cells and improved survival under bisphosphonate treatment. However, the anti-tumor effect of bisphosphonates remains controversial.
In this study we explored the glycolysis blocking properties of the bisphosphonate zoledronic acid in leukemia and breast cancer cells. Although, zoledronic acid had little effect at normoxic conditions, it significantly inhibited lactate production at reduced oxygen levels. Under these hypoxic conditions, that resemble the oxygenation levels in many tumors, zoledronic acid was also of significantly higher toxicity to the tumor cells. Moreover, we show that it strongly increased sensitivity to chemotherapy.
These results support the Warburg hypothesis and encourage further testing in vivo, to explore a potentially beneficial effect of zoledronic acid on the response to chemotherapy.

The authors declare no conflict of interest.

Not applicable

The datasets used in this study are openly available at [repository link] and the source code is available on GitHub at [GitHub link].

This work did not receive any external funding.