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Induction of apoptosis and/or necrosis following exposure to antitumour agents in a melanoma cell line, probably through modulation of Bcl-2 family proteins
Abstract
Malignant melanoma cells have been reported to be highly resistant to chemotherapeutic agents. To gain insight into the molecular mechanisms underlying chemotherapeutic drug resistance, we examined the role of the Bcl-2 family members Bcl-2 and Bax in cell death in the melanoma cell line G361 following stimulation with cisplatin (CDDP) or dacarbazine (DTIC). Trypan blue dye exclusion showed that both CDDP and DTIC induced death of G361 cells. Apoptotic and necrotic cell death could be distinguished by flow cytometry using combined staining with annexin V and 7-amino-actinomycin D (7-AAD). CDDP-induced cell death at a low concentration (0.6 micro g/ml) was mainly due to apoptosis (annexin V+/7-AAD-), while a mixture of apoptosis and secondary necrosis (annexin V+/7-AAD+) was found at a high concentration (6 micro g/ml). DTIC at the concentrations used induced only apoptosis. CDDP-induced apoptosis and secondary necrosis were accompanied by activation of caspase-3 and modulation of Bcl-2 family members Bcl-2 and Bax. On Western blotting Bax was seen to be upregulated with concomitant downregulation of Bcl-2. Flow cytometry, which enables measurement of protein at the single-cell level, revealed that Bcl-2+/Bax- cells were decreased, with a slight concomitant rise in Bcl-2-/Bax+ cells on stimulation with CDDP. These findings suggest that the chemotherapeutic agents CDDP and DTIC induce apoptosis and/or secondary necrosis depending on dose, probably involving the modulation of Bcl-2 family proteins.
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“Both DTIC and Temozolomide act through a common degradation product (MTIC).”
From Chemotherapeutic treatment efficacy and sensitivity are increased by adjuvant alternating electric fields (TTFields) (2009) · cites this paper as [16]
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Metadata
- Authors
- Shibuya, H., Kato, Y., Saito, M., Isobe, T., Tsuboi, R., Koga, M., Toyota, H., & Mizuguchi, J.
- Affiliations
- Tokyo Medical University (JP)
- Tokyo Medical University Hospital (JP)
- Corresponding author
- Mizuguchi, Junichiro
- Venue
- Melanoma Research
- Published
- 2003-10
- Volume
- 13
- Issue
- 5
- Pages
- 457-464
- ISSN
- 0960-8931 (ISSN-L)
- OpenAlex
- W2000352929
- Cited by
- 46
- References
- 39
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 2 · 2022: 1 · 2021: 2 · 2019: 1 · 2017: 1 · 2015: 2 · 2014: 2 · 2013: 1 · 2012: 2
- FWCI
- 0.92
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Melanoma Research (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Keywords
- melanoma, apoptosis, secondary necrosis, Bcl-2 family proteins, Bcl-2, Bax, cisplatin, dacarbazine, chemoresistance, caspase-3, dose-dependent cell death
- MeSH terms
- Antineoplastic Agents, Cell Survival, Cisplatin, Dacarbazine, Dactinomycin, Dose-Response Relationship, Drug, Coloring Agents, Enzyme Activation, Flow Cytometry, Fluorescent Dyes, Humans, Melanoma, Necrosis, Time Factors, Trypan Blue, Blotting, Western, Down-Regulation, Up-Regulation, Cell Death, Apoptosis, Annexin A5, Antineoplastic Agents, Alkylating, Proto-Oncogene Proteins c-bcl-2, Caspases, Cell Line, Tumor, Caspase 3
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