Anti-invasion, anti-proliferation and anoikis-sensitization activities of lapatinib in nasopharyngeal carcinoma cells.

Nasopharyngeal cancer (NPC) is a highly prevalent and invasive head and neck cancer in Asia. Disease recurrence and distant metastasis account for major NPC deaths. Therefore, more effective therapy is needed. Lapatinib, a dual tyrosine kinase inhibitor (TKI) against both EGFR and HER-2, has been known to exert potent antitumor activity against several cancer models. Given that both EGFR and HER-2 are co-expressed in NPC, we hypothesized that dual targeting of EGFR and HER-2 by this small molecule EGFR/HER-2 TKI would elicit anti-tumor activity in NPC. Using in vitro models of NPC, we demonstrated that lapatinib was able to efficiently inhibit the phosphorylation of both EGFR and HER-2. This was accompanied by significant growth inhibition of NPC cells (with maximal growth inhibition >90%). For the most lapatinib-sensitive cell line (HK1-LMP1, with IC(50) ∼ 600 nM), which harbored the highest levels of both EGFR and HER-2, inhibition of cell growth was associated G(0)/G(1) cell cycle arrest, marked PARP cleavage, caspase-3 cleavage, as well as significant downregulation of several important survival proteins (e.g. survivin, Mcl-1 and cyclin D1). NPC cells are intrinsically invasive. We found that lapatinib was able to inhibit cellular invasion of both HK1-LMP1 and HONE-1 cells. Furthermore, our data demonstrated for the first time that lapatinib harbored potent anoikis-sensitization activity (i.e. sensitizing cancer cells to detachment-induced apoptosis) in human cancer cells overexpressing both EGFR and HER-2 (HK1-LMP1 and HK1). Taken together, our findings suggest that lapatinib is a promising anti-cancer agent for NPC with anti-invasion and anoikis-sensitization activities.

An RNA-directed nucleoside anti-metabolite, 1-(3-C-ethynyl-beta-d-ribo-pentofuranosyl)cytosine (ECyd), elicits antitumor effect via TP53-induced Glycolysis and Apoptosis Regulator (TIGAR) downregulation.

1-(3-C-ethynyl-beta-d-ribo-pentofuranosyl)cytosine (ECyd) is a ribose-modified nucleoside analog of cytidine with potent anticancer activity in several cancers. The main antitumor mechanism of this promising RNA-directed nucleoside anti-metabolite is efficient blockade of RNA synthesis in cancer cells. Here, we examined the therapeutic potential of this RNA-directed anti-metabolite in in vitro models of nasopharyngeal cancer (NPC). In a panel of 6 NPC cell lines, ECyd effectively inhibited cellular proliferation at nM concentrations (IC(50): approximately 13-44nM). Moreover, cisplatin-resistant NPC cells were highly sensitive to ECyd (at nM concentration). The ECyd-mediated growth inhibition was associated with G(2)/M cell cycle arrest, PARP cleavage (a hallmark of apoptosis) and Bcl-2 downregulation, indicating induction of apoptosis by ECyd in NPC cells. Unexpectedly, ECyd-induced significant downregulation of TIGAR, a newly described dual regulator of apoptosis and glycolysis. More importantly, this novel action of ECyd on TIGAR was accompanied by marked depletion of NADPH, the major reducing power critically required for cell proliferation and survival. We hypothesized that ECyd-induced TIGAR downregulation was crucially involved in the antitumor activity of ECyd. Indeed, overexpression of TIGAR was able to rescue NPC cells from ECyd-induced growth inhibition, demonstrating a novel mechanistic action of ECyd on TIGAR. We demonstrated for the first time that an RNA-directed nucleoside analog, ECyd, exerts its antitumor activity via downregulation of a novel regulator of apoptosis, TIGAR. Moreover, ECyd may represent a novel therapy for NPC.

Chromosomal aberrations of multiple myeloma in Chinese patients at diagnosis: a study by combined G-banding and multicolor spectral karyotyping.

Cytogenetic investigation of multiple myeloma (MM) has been difficult by conventional methods and most of the data have been derived from western population where incidence of MM is much higher as compared to that of Asians. The current study represents the first report of chromosomal aberrations of multiple myeloma in Chinese. We investigated 25 consecutive Chinese patients with MM for chromosomal aberrations at diagnosis using G-banding and multicolor spectral karyotyping (SKY). Of the 21 patients successfully analyzed by G-banding, 11 patients revealed cytogenetic abnormalities showing complex numerical and structural aberrations, which were further characterized with SKY. An abnormal karyotype significantly associated with blastic MM was observed. Consistent with the western literature, structural rearrangements involving chromosomes 1, 6, 8, 19, numerical abnormalities of gains in chromosomes 9, 3, and 5, and losses in chromosomes 13 and 14 were observed. However, there were notably higher incidences of -22/22q- (4/11) and structural aberrations of chromosome X but a lower incidence of -X. The biological implications of these findings, if confirmed, deserve further evaluation.