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Effect of antitumor agents on cytotoxicity induction by sodium fluoride
Sufi Reza Md Morshed1, Takashi Tokunaga, Sumiko Otsuki
1Meikai Pharmaco-Medical Laboratory (MPL), Meikai University School of Dentistry, Sakado, Saitama, Japan.
Abstract:
We have recently found that sodium fluoride (NaF) induced apoptotic cell death in tumor cell lines. We investigated here whether 6 popular antitumor compounds modify the cytotoxic activity of NaF against human squamous cell carcinoma (HSC-2) and human promyelocytic leukemia (HL-60) cell lines. Cytotoxic concentrations of cisplatin, etoposide, doxorubicin or peplomycin (tentatively termed as Group I compounds), but not methotrexate and 5-FU (tentatively termed as Group II compounds), enhanced the cytotoxic activity of NaF. NaF and Group I compounds induced internucleosomal DNA fragmentation in HL-60 cells, whereas Group II compounds were inactive even in the presence of NaF. Most Group I compounds except doxorubicin (which induced DNA fragmentation less effectively than others) activated caspase 3 more efficiently than Group II compounds. Caspase 8 (involved in non-mitochondrial extrinsic pathway) and caspase 9 (involved in mitochondrial intrinsic pathway) were also activated, but to a much lesser extent. NaF reduced the glucose consumption at early stage, possibly by inhibition of glycolysis, whereas cisplatin and etoposide reduced the glucose consumption at later stage, suggesting that early decline of glucose consumption is rather specific to NaF.
Insights
Sodium fluoride (NaF) enhances the cancer-killing effects of certain chemotherapy drugs, like cisplatin and etoposide, by inducing apoptosis. This combination therapy shows promise for treating specific cancer cell lines.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Sodium fluoride (NaF) has demonstrated the ability to induce apoptotic cell death in various tumor cell lines.
- Understanding how established antitumor compounds interact with NaF is crucial for developing novel therapeutic strategies.
Purpose of the Study:
- To investigate the synergistic or antagonistic effects of six common antitumor agents when combined with sodium fluoride (NaF).
- To evaluate the impact of these combinations on the cytotoxicity against human squamous cell carcinoma (HSC-2) and human promyelocytic leukemia (HL-60) cell lines.
Main Methods:
- Cytotoxicity assays were performed using HSC-2 and HL-60 cell lines treated with NaF alone and in combination with six different antitumor compounds.
- Analysis of apoptotic cell death markers, including internucleosomal DNA fragmentation and caspase activation (caspase 3, 8, and 9).
- Assessment of cellular glucose consumption to understand metabolic changes induced by NaF and the combination therapies.
Main Results:
- Cytotoxic concentrations of cisplatin, etoposide, doxorubicin, and peplomycin (Group I) significantly enhanced NaF's cytotoxic activity.
- Methotrexate and 5-fluorouracil (Group II) did not enhance NaF's cytotoxic effects.
- NaF and Group I compounds induced DNA fragmentation and caspase 3 activation, with NaF specifically reducing glucose consumption at an early stage, suggesting glycolysis inhibition.
Conclusions:
- Certain chemotherapy agents, particularly cisplatin and etoposide, can potentiate the antitumor activity of sodium fluoride.
- The observed enhancement of cytotoxicity is associated with the induction of apoptosis, including DNA fragmentation and caspase activation.
- NaF's early inhibition of glucose consumption may represent a specific mechanism contributing to its cytotoxic effects, distinct from later effects seen with other chemotherapeutics.
