Carnosic Acid‐combined Arsenic Trioxide Antileukaemia Cells in the Establishment of NB4/SCID Mouse Model

Abstract

Despite great improvement in the treatment outcome of APL, treatment failure still sometimes occurs due to the toxicity of arsenic trioxide (ATO). Damage to the heart and liver often occurs even when the dose is lower than the therapeutic dose. Based on the results of cell experiments in vitro in this study, we investigated the synergistic activity of carnosic acid (CA) combined with ATO in the SCID mouse model of human promyelocytic leukaemia in vivo. A NB4/SCID mouse model was established in this study. The NB4/SCID mice were randomly divided into three treatment groups (CA alone, ATO alone and CA combined with ATO) and a control group based on factorial design. The evaluation indicators of the curative effect of the drugs included expressions of cleaved caspase-3, PTEN, p27 gene mRNA and proteins by immunohistochemistry, flow cytometry and Western blot analysis. The survival time was compared between the four groups. The results indicated that verification of the NB4/SCID mouse model was confirmed by histopathological examination. Compared with mice treated by CA or ATO alone, the mice in the combination of CA and ATO group had a higher rate of apoptosis, which was linked with expressions of cleaved caspase-3, PTEN, p27 gene mRNA and proteins. Also, the mice with the longest survival time were those treated with the combination of CA and ATO. In conclusion, the results of the present study indicated that CA and ATO in combination have strong synergistic antileukaemic effects on cell activity.

Telomere Length and Arsenic: Improving Animal Models of Toxicity by Choosing Mice With Shorter Telomeres

“…It would be especially helpful to create a genetically immunosupressed mouse line to mimic mice currently used cancer models (that can accept inoculation of human cancer cells). If we continue to see that larger doses of arsenicals 34 and combinations of drugs without lowering dose 30 increase the survival of these mice, then this part of the hypothesis is disproved, and telomere length is not a sufficient explanation for the reports of mice surviving longer when given seemingly more toxic doses.…”

“…28 To combat this unacceptable toxicity, one strategy, which is not unique to arsenical therapies, is to combine 2 drugs hoped to act in synergy at lower doses to achieve the same benefit with less toxicity. [29][30][31][32] One example of this adjuvant/combination strategy is the pairing of arsenic trioxide and carnosic acid. The combination of the 2 drugs, and each drug separately, has been tested on long-telomere mice, derived from BALB mice bred in captivity since at least 1913.…”

“…28 To combat this unacceptable toxicity, one strategy, which is not unique to arsenical therapies, is to combine 2 drugs hoped to act in synergy at lower doses to achieve the same benefit with less toxicity. 29 -32…”

“…The cocktail resulted in longer survival of mice and greater detected cellular apoptosis than observed with either drug alone. This led the authors to conclude that “the two drugs in combination have strong synergistic effects in anticancer activity” (p262) and that the combination may have potential “due to its anticipated safety and great potency.” 30 (p923)…”

“…Controls must be in place to rule out the explanation for apparent efficacy and safety that arise merely from increased general toxicity in mice. Otherwise, we risk moving these apparently safe and efficacious drugs into the clinic and finding more instances of “damage to the [human] heart and liver…even when the dose is lower than the therapeutic dose.” 30 (p259)…”