Activity of dolastatin 10 against small-cell lung cancer in vitro and in vivo: Induction of apoptosis and bcl-2 modification
Abstract
Purpose Dolastatin 10 is a natural cytotoxic peptide which acts through the inhibition of microtubule assembly. Studies have suggested that such agents can induce apoptosis in association with bcl-2 phosphorylation. Since bcl-2 overexpression is common in small-cell lung cancer (SCLC), we evaluated the activity of dolastatin 10 in SCLC cell lines and xenografts.Methods In vitro growth inhibition was evaluated with a standardized MTT assay and apoptosis with fluorescent microscopy and a TUNEL assay. Immunoblot analysis and phosphatase digestion were used to determine bcl-2 modification. In vivo activity was evaluated in subcutaneous and metastatic SCLC xenograft models in SCID mice.Results Dolastatin 10 had growth inhibitory activity against four SCLC cell lines (NCI-H69, -H82, -H446, -H510) with IC50 values ranging from 0.032 to 0.184 nM. All four cell lines exhibited evidence of apoptosis after 48 h of exposure to 1.3 nM dolastatin 10. Immunoblot analysis revealed that 1.3 nM dolastatin 10 altered the electrophoretic mobility of bcl-2 in NCI-H69 and -H510 cells within 16 h of treatment. Incubation of protein extract from dolastatin 10-treated NCI-H69 and -H510 cells with calcineurin resulted in the disappearance of the altered mobility species, suggesting dolastatin 10-induced bcl-2 phosphorylation. In in vivo studies, 450 microg/kg of dolastatin 10 IV x 2 given after intravenous injection of NCI-H446 cells completely inhibited tumor formation. In established subcutaneous NCI-H446 xenografts, 450 microg/kg of dolastatin 10 IV induced apoptosis in the majority of tumor cells within 96 h, resulting in a log10 cell kill of 5.2 and an increase in median survival from 42 to 91 days.Conclusions These findings suggest that dolastatin 10 has potent activity against SCLC and that the modulation of apoptotic pathways deserves further evaluation as an anticancer strategy.
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Dolastatin 10 and symplostatin 1 exhibit cytotoxic effects against human lung and breast cancer cell lines via Bcl-2 phosphorylation and caspase-3 protein activation.
“The linear pentapeptides dolastatin 10 and symplostatin 1 were isolated from Symploca spp. and exhibited cytotoxic effects against human lung and breast cancer cell lines, via both Bcl-2 phosphorylation and caspase-3 protein activation [183,184].”
From Marine Natural Products: A Source of Novel Anticancer Drugs (2019) · cites this paper as [184]
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Marine Natural Products: A Source of Novel Anticancer Drugs
Khalifa, S. A. M., Elias, N., Farag, M. A., Chen, L., Saeed, A., Hegazy, M.-E. F., Moustafa, M. S., Abd El-Wahed, A., Al-Mousawi, S. M., Musharraf, S. G., et al. (2019) · Marine Drugs · doi:10.3390/md17090491 · Cited by 555 · see citing works
“and exhibited cytotoxic effects against human lung and breast cancer cell lines, via both Bcl-2 phosphorylation and caspase-3 protein activation [183,184].”
BackgroundMarine cyanobacteria compounds with anticancer properties: A review on the implication of apoptosis
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- Authors
- Kalemkerian, G. P., Ou, X., Adil, M. R., Rosati, R., Khoulani, M. M., Madan, S. K., & Pettit, G. R.
- Affiliations
- Wayne State University (US)
- The Barbara Ann Karmanos Cancer Institute (US)
- Harper University Hospital (US)
- Arizona State University (US)
- Venue
- Cancer Chemotherapy and Pharmacology
- Published
- 1999-03-15
- Volume
- 43
- Issue
- 6
- Pages
- 507-515
- ISSN
- 0344-5704 (ISSN-L)
- 1432-0843
- OpenAlex
- W2000753870
- Cited by
- 84
- References
- 15
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 5 · 2023: 4 · 2022: 6 · 2021: 4 · 2020: 8 · 2019: 4 · 2017: 3 · 2016: 4 · 2015: 2 · 2014: 4 · 2013: 5 · 2012: 2
- FWCI
- 1.52
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Cancer Chemotherapy and Pharmacology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5p30es006639-15)
- National Cancer Institute (P30CA 22453, CA-44344-01A1-09, R35CA044344, P30CA022453)
- National Institute of Environmental Health Sciences (P-30-ES06639)
- Topics
- Health Sciences › Medicine › Oncology › Lung Cancer Research Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Immunology and Microbiology › Microbiology › Antimicrobial Peptides and Activities
- Keywords
- dolastatin 10, small cell lung cancer, apoptosis, Bcl-2 phosphorylation, microtubule assembly inhibition, calcineurin, tumor xenografts, NCI-H446 cells, anticancer agents
- MeSH terms
- Animals, Antineoplastic Agents, Female, Humans, Lung Neoplasms, Neoplasm Transplantation, Oligopeptides, Phosphorylation, Transplantation, Heterologous, Tumor Cells, Cultured, Mice, SCID, Apoptosis, Carcinoma, Small Cell, Proto-Oncogene Proteins c-bcl-2, Depsipeptides, Mice
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