Major differences between tumor and normal human cell fates after exposure to chemotherapeutic monofunctional alkylator

The major dilemma of cancer chemotherapy has always been a double-edged sword, producing resistance in tumor cells and life-threatening destruction of nontumorigenic tissue. Glioblastoma is the most common form of primary brain tumor, with median survival at 14 months after surgery, radiation and te...

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Bibliographic Details
Published in:PloS one 2013-09, Vol.8 (9), p.e74071
Main Authors: Gupte, Maithili, Tuck, Andrew N, Sharma, Vishal P, Williams, Kandace J
Format: Article
Language:English
Subjects:
Alkylation
Antineoplastic Agents, Alkylating - pharmacology
Apoptosis
Apoptosis Inducing Factor - metabolism
Apoptosis-inducing factor
Brain
Brain cancer
Brain tumors
Cancer
Caspase
Cell cycle
Cell Cycle - drug effects
Cell death
Cell Line
Cell Line, Tumor
Cell Lineage
Cell proliferation
Cells (Biology)
Cervical cancer
Cervical carcinoma
Cervix
Chemotherapy
Cleavage
Cytotoxicity
Dacarbazine - analogs & derivatives
Dacarbazine - pharmacology
Deoxyribonucleic acid
Development and progression
DNA
DNA damage
DNA methylation
Electrophoretic Mobility Shift Assay
Exposure
Fluorescent Antibody Technique, Indirect
Glioblastoma
Gliomas
Humans
Methylnitronitrosoguanidine - pharmacology
Mortality
Mutation
Neoplasm Proteins - metabolism
Neoplasms - metabolism
Neoplasms - pathology
Nuclei (cytology)
Proteins
Radiation
Senescence
Surgery
Temozolomide
Toxicity
Tumor cell lines
Tumor cells
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Summary:The major dilemma of cancer chemotherapy has always been a double-edged sword, producing resistance in tumor cells and life-threatening destruction of nontumorigenic tissue. Glioblastoma is the most common form of primary brain tumor, with median survival at 14 months after surgery, radiation and temozolomide (monofunctional alkylator) therapy. Treatment failure is most often due to temozolomide-resistant tumor growth. The underlying basis for development of tumor cell resistance to temozolomide instead of death is not understood. Our current results demonstrate that both cervical carcinoma (HeLa MR) and glioblastoma (U251) tumor cells exposed to an equivalent chemotherapeutic concentration of a monofunctional alkylator undergo multiple cell cycles, maintenance of metabolic activity, and a prolonged time to death that involves accumulation of Apoptosis Inducing Factor (AIF) within the nucleus. A minority of the tumor cell population undergoes senescence, with minimal caspase cleavage. Surviving tumor cells are comprised of a very small subpopulation of individual cells that eventually resume proliferation, out of which resistant cells emerge. In contrast, normal human cells (MCF12A) exposed to a monofunctional alkylator undergo an immediate decrease in metabolic activity and subsequent senescence. A minority of the normal cell population undergoes cell death by the caspase cleavage pathway. All cytotoxic events occur within the first cell cycle in nontumorigenic cells. In summation, we have demonstrated that two different highly malignant tumor cell lines slowly undergo very altered cellular and temporal responses to chemotherapeutic monofunctional alkylation, as compared to rapid responses of normal cells. In the clinic, this produces resistance and growth of tumor cells, cytotoxicity of normal cells, and death of the patient.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0074071