A negative adaptive response is expressed in peripheral blood lymphocytes that are exposed to mitomycin C and cycloheximide
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Purpose: Mitomycin C (MMC) and cycloheximide (CHX) are known for their apoptotic and antitumor activity. CHX is also known for its property to inhibit protein synthesis and to reduce cytotoxicity of various antitumor drugs, i.e. inducing an adaptive survival response (ASR). The purpose of this study was to evaluate the effect of ASR induced by CHX in cells exposed to clastogenic doses of MMC. Materials and methods: In all experiments we used human peripheral blood lymphocytes of 10 healthy male non-smokers, 25-35 years of age. Three groups were established. One control group or PBS-treated group. Two distinctive experimental groups were based on the induction or non-induction of ASR by CHX, i.e. one with MMC alone and a second one with CHX and MMC. The effect of ASR was induced by CHX at a dose of 10 μg/ml. MMC was used in 3 dose levels: 0.05 μM, 0.15 μM and 0.6 μM. To evaluate ASR induced by CHX in cells exposed to MMC we used the cytokinesis-blocked micronucleus test (CBMN) in vitro.... Results: CHX at a dose of 10 mg/ml induced an ASR in human peripheral blood lymphocytes of healthy subjects exposed to increasing doses of MMC. CHX induced statistically highly significant difference (p lt 0.001) in the nuclear division index (NDI) compared to cells exposed to MMC alone. Genotoxicity of MMC measured by the percentage of micronuclei in binuclear (BN) cells was not elevated in the presence of CHX. Also, the increase in the NDI was correlated with the decrease in nuclear fragmentation (NF). Conclusion: The observed differences in NF and the NDI between the two groups showed that ASR to MMC induced by CHX could be a consequence of inhibition of apoptosis. We argue that adaptation (pro-life processes) can overwhelm its positive aspects (antimutagenic and anticarcinogenic) by increasing the population of cells with chromosome aberrations (chromosome instability) by apoptotic inhibition. CHX disturbs the apoptotic signal. Understanding that ASR can act as a pro-survival process leading to inhibition of apoptosis shall enhance in the future our knowledge of anticarcinogenesis, thus utilizing new paths for better treatment of cancer.
Keywords:Adaptive survival response / Apoptosis / Cycloheximide / Micronucleus test / Mitomycin-C
Source:Journal of BUON, 2005, 10, 1, 111-117
- Balkan Union of Oncology (B.U.ON.)