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Apoptosis modulators as cancer therapeutics
1Ontario Cancer Institute, Princess Margaret Hospital, Toronto, Canada. lpenn@oci.utoronto.ca
Abstract:
In the past ten years a wealth of fundamental knowledge delineating the molecular mechanism(s) of apoptosis has emerged, and can now be exploited to identify novel apoptotic modulators for the treatment of cancer. Two distinct yet complimentary classes of non-genotoxic agonists that can selectively kill tumor cells are discussed; agents that target 'classical' and 'atypical' apoptotic signaling pathways. The goal of agents targeting classical apoptosis and survival pathways is to directly modulate key apoptotic regulators such as Bcl-2, Akt/PKB, and p53. The aim of agents targeting atypical apoptotic pathways is to target signaling cascades whose inhibition remains non-lethal in normal cells, yet is suicidal in tumor cells. Such compounds presently under development include inhibitors of heat shock protein 90, histone deacetylases and HMG-CoA reductase. Both classes of apoptotic modulators have merit and identification of additional agonists of this nature will provide the many diverse cytotoxic agents that are required to combat the many diseases we call cancer.
Insights
Scientists are developing new cancer treatments by targeting cell death pathways. These novel apoptotic modulators selectively kill tumor cells through classical or atypical signaling, offering diverse therapeutic strategies.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Significant advancements in understanding apoptosis molecular mechanisms over the past decade.
- Apoptosis (programmed cell death) is a key target for cancer therapy.
Purpose of the Study:
- To review novel non-genotoxic apoptotic modulators for cancer treatment.
- To discuss agents targeting both classical and atypical apoptosis pathways.
Main Methods:
- Focus on agents modulating classical apoptosis regulators (e.g., Bcl-2, Akt/PKB, p53).
- Exploration of agents targeting atypical apoptosis pathways (e.g., HSP90, HDAC, HMG-CoA reductase inhibitors).
Main Results:
- Two distinct classes of apoptotic modulators show promise.
- Targeting atypical pathways offers selective tumor cell lethality with minimal normal cell impact.
Conclusions:
- Both classical and atypical apoptotic modulators hold therapeutic merit.
- Development of diverse cytotoxic agents is crucial for combating various cancers.