Exploring the apoptotic potential of ABT-737, as a means to sensitize breast cancer cells to certain chemotherapies (doxorubicin)

Many cancers possess the ability to override the normal apoptotic mechanisms that would usually lead to cell death. This leads to resistance to therapeutic modalities such as radiation and chemotherapy.

The balance between members of the bcl-2 family, including both pro apoptotic and anti-apoptotic, determines the fate of many cells. In cancer, the normal ratios of these members has been disrupted to favour survival. In breast cancer several studies have shown bcl-2, bcl-w, bcl-xl and mcl-1 to be up regulated to varying degrees, and highest levels have been linked to poorer prognosis.

In recent years, to sensitise cancer cells to apoptotic inducing therapies, several compounds have been developed to reduce the anti-apoptotic effect of Bcl-2 family members and thus allow stimulation of apoptosis in cancer cells. One such compound, ABT-737, is proving to have beneficial effects in multiple myeloma, and other blood borne cancers. Its effectiveness on breast cancer, which also displays a substantial increase in bcl-2 family members, has been limited. ABT-737, was designed to displace BH3 only proteins from bcl-xl (and also bcl-2 and bcl-w) thus allowing the mitochondrial outer membrane permeabilization to occur, and thus apoptosis.

Our research combines BH3-mimetics (e.g. ABT-737) with doxorubicin in an attempt to enhance apoptosis.  In particular we wish to unravel the time-dependent molecular changes in response to this combination to understand the mechanism of action and possible reasons for failure of this combination therapy.