Unraveling biologic therapy for Bcl-2-expressing malignancies
Section snippets
Bcl-2
The bcl-2 (B-cell lymphoma/leukemia-2) oncogene was initially recognized for its role in blocking apoptosis in certain B-cell lymphomas. More recently, Bcl-2 has been shown to also be overexpressed in most types of cancer, including breast, colorectal, lung, and prostate cancers, as well as melanoma. Bcl-2 belongs to a family of evolutionarily conserved proteins that is functionally subdivided into proapoptotic (eg, Bax, Bak) and anti-apoptotic members (eg, Bcl-2, Bcl-XL). Bcl-2 family members
Oblimersen: Bcl-2 antisense
Bcl-2 antisense oligonucleotides have been successfully used to block expression of Bcl-2 both in vitro and in vivo and to lift the blockage of apoptosis in cancer cells.1 Antisense oligonucleotides are short, synthetic, single-stranded DNA sequences that bind to mRNA; this binding accelerates mRNA decay and thus effectively blocks protein synthesis.1 A range of antisense oligonucleotides for Bcl-2 inhibition have been studied, and oblimersen (Genasense, formerly G3139; Genta, Inc, Berkeley
Other therapeutics that downregulate Bcl-2
Another approach for downregulating Bcl-2 activity in cancer cells is to target the mBzR (also called the peripheral benzodiazepine receptor). This 18-kd transmembrane-spanning protein localized to the outer mitochondrial membrane shares a close physical association with constituents of the MPTP. Two small molecules that block the activity of the mBzR are currently being investigated. PK11195, an isoquinoline carboxamide, specifically binds the mBzR with nanomolar affinity. This binding affects
Other antiapoptotic targets
In addition to Bcl-2, it may be necessary to target other anti-apoptotic molecules that inhibit apoptosis in the treatment of certain cancers. For example, NF-κB, which is part of the ubiquitin-proteasome pathway, is overexpressed in many types of malignancies, leading to chemoresistance via the MPTP and the caspase-9 pathway. Even in the presence of Bcl-2 inhibition, NF-κB can potentially block the caspase cascade. Therefore, in cancer cells overexpressing Bcl-2 and demonstrating NF-κB
Conclusion
A critical factor for treating chemotherapy-resistant malignancies is controlling mitochondrial permeability, which is essentially a gatekeeper of apoptosis. In the future, it is expected that biologic therapies that target the apoptotic machinery and the MPTP will be based on those currently investigated in or considered for clinical trials. An improved understanding of malignant cell biology will provide further opportunities to progress from chemotherapy-based treatments to biologic
References (30)
- et al.
The overexpression of Bax produces cell death upon induction of the mitochondrial permeability transition
J Biol Chem
(1998) - et al.
Chemosensitisation of malignant melanoma by BCL2 antisense therapy
Lancet
(2000) - et al.
PK11195, a ligand of the mitochondrial benzodiazepine receptor, facilitates the induction of apoptosis and reverses Bcl-2-mediated cytoprotection
Exp Cell Res
(1998) - et al.
PK11195, a peripheral benzodiazepine receptor ligand, chemosensitizes acute myeloid leukemia cells to relevant therapeutic agents by more than one mechanism
Leuk Res
(2002) - et al.
Prognostic values of galectin-3 and the macrophage migration inhibitory factor (MIF) in human colorectal cancers
Mod Pathol
(2003) - et al.
Controlling the mitochondrial gatekeeper for effective chemotherapy
Br J Haematol
(2000) Biochemical and cellular mechanisms of toxic liver injury
Semin Liver Dis
(2002)- et al.
Bcl-2 antisense oligodeoxynucleotide therapy of Epstein-Barr virus-associated lymphoproliferative disease in severe combined immunodeficient mice
Cancer Res
(2000) - et al.
Phase I clinical and pharmacokinetic study of bcl-2 antisense oligonucleotide therapy in patients with non-Hodgkin’s lymphoma
J Clin Oncol
(2000) - et al.
A phase I-II study with dacarbazine and BCL-2 antisense oligonucleotide G3139 (GENTA) as a chemosensitizer in patients with advanced malignant melanoma
Proc Am Soc Clin Oncol
(1999)
A phase I/IIA dose-escalating trial of bcl-2 antisense (G3139) treatment by 14-day continuous intravenous infusion (CI) for patients with androgen-independent prostate cancer or other advanced solid tumor malignancies
Proc Am Soc Clin Oncol
Tumor regression of human breast carcinomas by combination therapy of anti-bcl-2 antisense oligonucleotide and chemotherapeutic drugs
Proc Am Assoc Cancer Res
A phase I study of BCL-2 antisense G3139 (GENTA) and weekly docetaxel in patients with advanced breast cancer and other solid tumors
Proc Am Soc Clin Oncol
Bcl-2 antisense (Genasense) induces apoptosis and potentiates activity of both cytotoxic chemotherapy and rituximab in primary CLL cells
Blood
Genasense targeting Bcl-2 protein expression enhances the biological anti-tumor activity of rituximab against non-Hodgkins (NHL) cell lines and lymphoma xenografts
Blood
Cited by (11)
β-Glucan: A dual regulator of apoptosis and cell proliferation
2021, International Journal of Biological MacromoleculesCitation Excerpt :Bcl-2 family of proteins comprise both pro-apoptotic (BAX, BAD and BAK) and anti-apoptotic proteins (Bcl-2 and Bcl-w) [104]. Elevated levels of Bcl-2 proteins have been found in many cancers [105]. Appropriate signaling in apoptotic pathways is important for normal homeostasis in cells and any disruption in this leads to cancer [106].
Grafting of Polysaccharides: Recent Advances
2018, Biopolymer Grafting: Synthesis and PropertiesCancer therapeutics: Targeting the dark side of Myc
2005, European Journal of CancerCombination therapy in combating cancer
2017, OncotargetABT-737, a BH3 mimetic, induces glutathione depletion and oxidative stress
2009, Cancer Chemotherapy and PharmacologyIncidence of TCR and TCL1 gene translocations and isochromosome 7q in peripheral T-cell lymphomas using fluorescence in situ hybridization
2008, American Journal of Clinical Pathology
- 1
Dr Cotter has received honoraria from Aventis, Genta, and Genentech BioOncology.