title: Enhanced anti-cancer effect of a phosphatidylinositol-3 kinase inhibitor and doxorubicin on human breast epithelial cell lines with different p53 and oestrogen receptor status.
abstract: New efforts are being focused on signalling pathways as targets for cancer therapy. This particular study was designed to investigate whether blockade of the phosphatidylinositol 3OH-kinase (PI3K) pathway (a survival/anti-apoptosis pathway, overexpressed in various tumours) could sensitise human breast cancer cells to the effect of chemotherapeutics. Doxorubicin (Dox) and LY294002 (LY, a PI3K inhibitor) were used individually or in combination on MDA-MB-231 (p53 mutant, ER-), T47D (p53 mutant, ER+), and MCF-7 (p53 wildtype, ER+) human breast cancer cell lines, and on 184A1, a nonmalignant human breast epithelial cell line (p53 wildtype, ER-). Each drug showed time- and dose-dependent growth inhibition of cell proliferation on all 4 cell lines. The combination of Dox+LY resulted in enhanced cell growth inhibition in MDA-MB-231 and T47D cells, and additive inhibition in MCF-7 and 184A1 cells. Cell cycle analysis showed that Dox+LY enhanced the arrest of MDA-MB-231 and T47D cells in G2 with the appearance of a sub-G1 peak indicating apoptosis/necrosis, a notion supported by enhanced depolarisation of mitochondrial membrane potential in these cell types. The combination also caused a greater additive increase in Cyclin B1. Thus, the synergistic effect of the combination on cell proliferation in some, but not all, breast cancer cells may be through enhanced induction of both G2 arrest and apoptosis, in which p53 may play a role. Substantially lower doses of doxorubicin could be used with low doses of inhibitors of the PI3K pathway, without compromising the anti-cancer effect, but also lowering detrimental side-effects of doxorubicin. This study supports the notion that survival signalling pathways offer special targets for chemotherapy in cancer.
authors.affiliation: Cell Signalling Group, Academic Unit of Endocrinology, Section of Endocrinology and Reproduction, University of Sheffield Medical School, Beech Hill Road, Sheffield, S10 2RX, United Kingdom.
authors.forename: Yan A
authors.initials: YA
authors.lastname: Wang
authors.forename: Stuart K
authors.initials: SK
authors.lastname: Johnson
authors.forename: Barry L
authors.initials: BL
authors.lastname: Brown
authors.forename: Leeza M
authors.initials: LM
authors.lastname: McCarragher
authors.forename: Kaltoom
authors.initials: K
authors.lastname: Al-Sakkaf
authors.forename: Janice A
authors.initials: JA
authors.lastname: Royds
authors.forename: Pauline R M
authors.initials: PR
authors.lastname: Dobson
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D002453:Cell Cycle; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002867:Chromones / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005434:Flow Cytometry; D006801:Humans; D042361:Mammary Glands, Human / Q000187:drug effects* / Q000378:metabolism; D008564:Membrane Potentials; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D009025:Morpholines / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011960:Receptors, Estrogen / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D002867:Chromones; D004791:Enzyme Inhibitors; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011960:Receptors, Estrogen; D016159:Tumor Suppressor Protein p53; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D004317:Doxorubicin