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Targeting calmodulin for the development of novel cancer chemotherapeutic agents
1Department of Medicine, Yale University School of Medicine, New Haven, Connecticut 06510.
Abstract:
The calcium-messenger system is involved in the regulation of cellular proliferation. Alterations in any of the components of this system could lead to states of abnormal cellular proliferation. We have focused our attention on drugs that antagonize the actions of calmodulin, a central calcium regulatory protein. Following purification of calmodulin from normal and malignant cells by preparative polyacrylamide gel electrophoresis, we determined the sensitivity of the molecule to several classes of calmodulin antagonists and found a direct correlation between antagonism of calmodulin and inhibition of cellular viability. Fluphenazine mustard was shown to be an irreversible calmodulin antagonist and an extremely potent inhibitor of leukemic cell growth. Dequalinium and rhodamine-123, drugs selectively accumulated in malignant cells, were found to be potent calmodulin antagonists, and inhibited the growth of C6 astrocytoma cells. Further studies led to the observation that the combination of calmodulin antagonists with bleomycin produced synergistic cell-kill that was related to enhanced DNA damage. The combination of trifluoperazine and bleomycin was safely administered to 19 heavily pre-treated cancer patients, of whom four had excellent clinical responses. These studies suggest that calmodulin might be an important target for the development of new antineoplastic drugs.
Insights
Targeting calmodulin, a key calcium regulatory protein, with specific drugs shows promise for cancer treatment. Antagonizing calmodulin effectively inhibits cancer cell growth and enhances chemotherapy effectiveness, suggesting new therapeutic strategies.
Area of Science:
- Biochemistry
- Cell Biology
- Pharmacology
Background:
- The calcium-messenger system regulates cellular proliferation, and its dysregulation can lead to abnormal growth.
- Calmodulin is a central calcium regulatory protein within this system.
- Targeting calmodulin offers a potential strategy for developing antineoplastic drugs.
Purpose of the Study:
- To investigate the role of calmodulin antagonists in inhibiting cellular proliferation.
- To evaluate the efficacy of specific calmodulin antagonists, including fluphenazine mustard, dequalinium, and rhodamine-123, against cancer cells.
- To explore the synergistic effects of calmodulin antagonists combined with chemotherapy agents like bleomycin.
Main Methods:
- Purification of calmodulin from normal and malignant cells using preparative polyacrylamide gel electrophoresis.
- Assessment of calmodulin antagonist sensitivity and correlation with cellular viability.
- In vitro studies on C6 astrocytoma cells and leukemic cells.
- Clinical evaluation of combined trifluoperazine and bleomycin therapy in cancer patients.
Main Results:
- A direct correlation was observed between calmodulin antagonism and inhibition of cellular viability.
- Fluphenazine mustard demonstrated irreversible calmodulin antagonism and potent inhibition of leukemic cell growth.
- Dequalinium and rhodamine-123, selectively accumulated in malignant cells, inhibited C6 astrocytoma cell growth.
- Combination therapy with calmodulin antagonists and bleomycin showed synergistic cell-kill, linked to enhanced DNA damage.
- Clinical trials indicated safe administration and excellent responses in some cancer patients receiving trifluoperazine and bleomycin.
Conclusions:
- Calmodulin is a significant target for novel antineoplastic drug development.
- Calmodulin antagonists, particularly when combined with chemotherapy, show potential in cancer treatment.
- Further research into calmodulin-targeted therapies could lead to improved cancer treatment strategies.