One of the most effective ways to combat different types of cancer is through early diagnosis and administration of effective treatment, followed by efficient monitoring that will allow physicians to detect relapsing disease and treat it at the earliest possible time. Apoptosis, a normal physiological form of cell death, is critically involved in the regulation of cellular homeostasis. Dysregulation of programmed cell death mechanisms plays an important role in the pathogenesis and progression of cancer as well as in the responses of tumours to therapeutic interventions. Many members of the BCL2 (B-cell CLL/lymphoma 2; Bcl-2) family of apoptosis-related genes have been found to be differentially expressed in various malignancies, and some are useful prognostic cancer biomarkers. We have recently cloned a new member of this family, BCL2L12, which was found to be differentially expressed in many tumours. Most of the BCL2 family genes have been found to play a central regulatory role in apoptosis induction. Results have made it clear that a number of coordinating alterations in the BCL2 family of genes must occur to inhibit apoptosis and provoke carcinogenesis in a wide variety of cancers. However, more research is required to increase our understanding of the extent to which and the mechanisms by which they are involved in cancer development, providing the basis for earlier and more accurate cancer diagnosis, prognosis and therapeutic intervention that targets the apoptosis pathways. In the present review, we describe current knowledge of the function and molecular characteristics of a series of classic but also newly discovered genes of the BCL2 family as well as their implications in cancer development, prognosis and treatment.

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Most apoptosis-related genes regulate cellular fate as a response to anticancer drugs. Modulations at the mRNA levels of such genes often correlate with the sensitivity of various types of cancer cells to chemotherapeutic reagents. The drugs cisplatin, carboplatin, and doxorubicin exhibit anticancer activity, the mechanism of which is not yet completely clarified, although they are known to modulate the expression of several genes including apoptosis-related genes, such as members of the BCL2 (Bcl-2) family. In order to define the significance of the expression patterns of such genes as a response to anticancer drug cytotoxic activity, we studied the possible alterations in the mRNA expression levels of various apoptosis-related genes, including the new member, BCL2L12, after cell treatment with distinct anticancer drugs (cisplatin, carboplatin, and doxorubicin), in the breast cancer cell line, MCF-7. The kinetics of cell toxicity was evaluated by the MTT method, whereas the expression levels of distinct apoptosis-related genes were analyzed by reverse transcriptase polymerase chain reaction (RT-PCR), using gene-specific primers. The percentage of nonviable cells was upregulated with increasing concentrations and cell exposure time to the different anticancer drugs. Distinct modulations of apoptosis-related genes, at the mRNA level, were also observed. However, further work is required in order to ascertain whether the mRNA expression profile of such genes may provide evidence for their contribution to more specific and sensitive prediction of breast cancer response to treatment and therefore the rationale for individualized, more appropriate, and successful treatment.

Apoptosis is a type of programmed cell death involved in many crucial biological processes. It represents the basic mechanism for the action of chemotherapeutic agents, such as doxorubicin and carboplatin. Both are able to cause cell death through the induction of apoptosis in the human leukemic cell line HL-60. We investigated the possible alterations in the expression of apoptosis-related genes, including the novel BCL2L12 gene, which was recently cloned in our group. The kinetics of apoptosis induction and cell toxicity was investigated by DNA laddering and by the MTT method, respectively. Total RNA was extracted and cDNA was prepared by reverse transcription. BCL2 , BAX , FAS , caspase-9, caspase-3 and BCL2L12 were amplified by PCR. Overexpression of FAS , BCL2L12 and caspase-3 was observed after treatment of HL-60 cells for 3 or 6 h with carboplatin, while their expression was decreased after a 12-h treatment, demonstrating that these genes may take part in the early stages of apoptosis. Overexpression of the same genes was also observed after 6 h of treatment with doxorubicin (concomitantly with DNA laddering). In the case of carboplatin-induced apoptosis we detected down-regulation of BAX , BCL2 and caspase-9, whereas in the case of doxorubicin, BAX and BCL2 remained at control levels and caspase-9 was increased.