Abstract
Arsenic Trioxide (ATO) is widely acknowledged as the treatment of choice for Acute Promyelocytic Leukemia (APL). It is a “two-sided” drug since it can induce differentiation or kill APL and other tumor cells according to the dosage. Part of the cytotoxic effects of ATO on APL cells is due to its pro-oxidant activity, a characteristic which ATO shares with a number of other compounds, including high doses of ascorbate (ASC). In a comparative investigation on the cytotoxic effects of both ATO and ASC on HL60 (APL) cell lines, in Vitro, we have been able to confirm the known cytotoxic effects of ATO, but, more importantly, we have demonstrated that ASC is significantly more effective than ATO, in killing these cancer cells in Vitro, when the concentrations are maintained within the millimolar (mM) range, i.e. the range of plasma concentrations at which ASC induces oxidative damage to tumor cells. Since these plasma levels can be reached only by the intravenous administration of high doses of ASC, we propose that intravenous high doses of ASC may represent a potentially revolutionary new approach in the management of APL.
Highlights
In a comparative investigation on the cytotoxic effects of both Arsenic Trioxide (ATO) and ASC on HL60 (APL) cell lines, in vitro, we have been able to confirm the known cytotoxic effects of ATO, but, more importantly, we have demonstrated that ASC is significantly more effective than ATO, in killing these cancer cells in vitro, when the concentrations are maintained within the millimolar range, i.e. the range of plasma concentrations at which ASC induces oxidative damage to tumor cells
The two tailed “p” value of the difference in the percentage of live cells between ASC and ATO suggests that ASC 1, and 3 mM is more effective than ATO 2, and 4 μg/ml, respectively, in reducing the survival of HL60 cells in culture even though the difference does not appear statistically significant
Four periods have been identified, in the treatment of Acute Promyelocytic Leukemia (APL), which have marked a progressive improvement in the cure of this disease, namely: 1) chemotherapy (CT) alone, from 1957 to 1985; 2) all-trans retinoic acid (ATRA), introduced in 1985; 3) Arsenic Trioxide (As2O3-ATO) introduced in the mid 1990s; 4) Combination of ATRA and ATO, in 1998
Summary
Studies on HL60 (human promyelocytic leukemia) cell line, have shown that ATO can be viewed as a twosided drug, inducing either differentiation or apoptosis on these cell lines [10], according to the dosage employed. These data have been confirmed by studies on retinoblastoma cell lines, showing that in low doses (≤1 μM) it induces differentiation, while in high doses (≥2 μM) it behaves as a pro-apoptotic drug and effectively inhibit tumor formation in vitro [11]. ATO shares this pro-oxidant activity with a number of other compounds, including sodium ascorbate (ASC) administered in high doses by intravenous injection [16,17,18,19,20]
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