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Abstract
Chemotherapy drugs have been prescribed for the systemic treatment of cancer. We selected three chemotherapy drugs, including methotrexate, mitomycine C and vincristine to inhibit the proliferation of HT1080 human fibrosarcoma cells in S, G2 and M phases of the cell cycle respectively. These chemotherapy drugs showed significant toxicity and growth inhibition to the cancer cells measured by MTT assay. After treated with a 50% inhibitory dosage for 48 hours, these cancer cells showed significant accumulation of cardiolipin (CL), which was a reverse trend of the nutritional deficiency induced arrest at G1 phase. The quantity of each CL species was further semi-quantitated by HPLC-ion trap mass spectrometer. Methotraxate treatment caused unique increases of acyl chain length on CL, which were the opposite of the serum starvation, mitomycine C and vincristine treatments. Although mitomycine C and vincristine have different mechanisms to induce cell cycle arrest, these two drugs displayed similar effects on decreasing chain length of CL. Continuation of CL synthesis during cell cycle arrest indicated the chemotherapy drugs resulting in the discoordination of the mitochondrial life cycle from the cell cycle and thus caused the accumulation of CL. These finding reveals that the pre-remodeling nascent CL accumulates during the methotraxate induced arrest; however, the post-remodeling mature CL accumulates during the mitomycine C and vincristine induced arrest after the synthesis phase.
Highlights
Chemotherapy drugs are often designed to interfere with cell growth signals, inhibit enzymatic activities or compete with the required materials for replication in various phases of the cell cycle to achieve cell cycle arrest and prevent cancer progression [1,2,3]
We hypothesized that the discoordination of the two cycles would occur after chemotherapy drug induces cell cycle arrest
The cell cycle can be inhibited in the drug treated cancer cells, but the mitochondrial life cycle is not arrested or responds
Summary
Chemotherapy drugs are often designed to interfere with cell growth signals, inhibit enzymatic activities or compete with the required materials for replication in various phases of the cell cycle to achieve cell cycle arrest and prevent cancer progression [1,2,3]. When cells sustain DNA damage, nutritional deficiency or oxidative stress, the cell cycle is arrested at the check points. The cell cycle is highly regulated by Cyclin-CDK complex [4,5,6]. Inhibition of the CDK (s) by CDK interacting protein/kinase inhibitory protein family (cip/kip) [7] and the inhibitor of kinase 4/alternative reading frame family (INK4a/ARF) [8,9] would trigger cell cycle arrest.
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