Poly(ADP-ribose) polymerase-1 (PARP-1) is a new potential target for anticancer drug discovery. A series of bromophenol−thiosemicarbazone hybrids as PARP-1 inhibitors were designed, synthesized, and evaluated for their antitumor activities. Among them, the most promising compound, 11, showed excellent selective PARP-1 inhibitory activity (IC 50 = 29.5 nM) over PARP-2 (IC 50 > 1000 nM) and potent anticancer activities toward the SK-OV-3, Bel-7402 and HepG2 cancer cell lines (IC 50 = 2.39, 5.45, and 4.60 μM), along with inhibition of tumor growth in an in vivo SK-OV-3 cell xenograft model. Further study demonstrated that compound 11 played an antitumor role through multiple anticancer mechanisms, including the induction of apoptosis and cell cycle arrest, cellular accumulation of DNA double-strand breaks, DNA repair alterations, inhibition of H 2 O 2triggered PARylation, antiproliferative effects via the production of cytotoxic reactive oxygen species, and autophagy. In addition, compound 11 displayed good pharmacokinetic characteristics and favorable safety. These observations demonstrate that compound 11 may serve as a lead compound for the discovery of new anticancer drugs.

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The PHLPP (pleckstrin homology [PH] domain leucine rich repeat protein phosphatase) family, which represents a family of novel Ser/Thr protein phosphatases, is composed of 2 members: PHLPP1 and PHLPP2. PHLPPs partake in diverse cellular activities to exhibit their antitumor and metastasis suppressor functions. It is necessary to investigate the expression patterns of PHLPP1 and PHLPP2 in hypopharyngeal squamous cell carcinomas (HSCCs) and clarify their clinical significance. A total of 138 patients with primary HSCC who underwent curative surgical treatment as an initial treatment were enrolled in this study. A total of 138 HSCC specimens and 64 adjacent noncancerous mucosal epithelial tissues were collected. The expression levels of PHLPP1 and PHLPP2 were examined by quantitative reverse transcription polymerase chain reaction and immunohistochemistry assays. Correlations between clinicopathological parameters of the patients were further evaluated. PHLPP1 and PHLPP2 mRNA transcript levels were significantly lower in tumor samples than in paired adjacent nontumor mucosae (P<0.0001, both). Positive correlations were observed between the mRNA levels of PHLPP1 and PHLPP2 in HSCC tissues (correlation coefficient r = 0.678, P<0.001) and in adjacent nontumor mucosae (r = 0.460, P<0.001). The majority of the noncancerous tissues showed high expression levels of PHLPP1 (87.5%, 56/64) and PHLPP2 (85.9%, 55/64). However, the expressions of PHLPP1 and PHLPP2 were significantly decreased in 83.3% (115/138) and 82.6% (114/138) of tumor tissues, respectively (P<0.0001, both). The expressions of both PHLPP isoforms were significantly related to the tumor clinical stage, differentiation, and cervical lymph node metastasis (P<0.05, all). It was PHLPP1 but not PHLPP2 that was significantly related to the tumor T stage. Low PHLPP1 and PHLPP2 expressions were associated with poor overall survival (OS) in HSCC patients (P = 0.004, P = 0.008, respectively). Multivariate analysis revealed that PHLPP1 was an independent prognostic factor for OS. This study indicates that, in HSCC, aberrant expressions of PHLPP1 and PHLPP2 are common events, and loss of PHLPPs might identify patients with poor prognostic outcomes.

Aim of the investigation was to develop folate-functionalized lipid nanoemulsion (LNE) comprising chemo-radiotherapeutics for targeted delivery to nasopharyngeal carcinoma (NPC). Soy lecithin nanoemulsion of doxorubicin (Dox) and yittrium-90 (90Y) was prepared by nanoprecipitation using ultrasonic homogenization technique followed by folic acid conjugation. Nanoemulsion (Dox-LNE) was characterized as positively charged (zeta potential), spherical shape (transmission electron microscopy) nano-droplets of uniform size distribution (polydispersity index). No significant variation in parameters such as particle size, zeta potential, and polydispersity index was observed when the stability of Dox-LNE was assessed during long-term storage at room temperature and at 8000 rpm, 121°C temperature, and 5000 time dilution in water. In vitro release of Dox from Dox-LNE was observed to be controlled for at least 48 h. Folate decoration over Dox-LNE surface (FD-Dox-LNE) and incorporation of 90Y in FD-Dox-LNE (FD-Dox + 90Y-LNE) changed droplet size up to 50 nm; however, surface charge of Dox-LNE did not change significantly. FD-Dox + 90Y-LNE inhibited growth of cancerous cell line like CNE1 (folate receptor rich) in vitro and alleviated tumor volume in NPC-induced nude mice significantly as compared to Dox + 90Y-LNE. Massive necrosis and hemorrhage of CNE1 cells were observed by FD-Dox + 90Y-LNE (89.9%); however, inhibition of growth of nasal epithelial cells (RPMI 2650; folate deficient) by FD-Dox + 90Y-LNE and Dox + 90Y-LNE was observed to be 21.5 and 43.65%, respectively. The investigation highlights the vast utility of folate-decorated lipid emulsion in delivering chemo-radiotherapeutics to the specific NPC site. FD-Dox + 90Y-LNE might offer a cost-effective, safe, efficacious, and clinically pertinent option to the available therapeutics.

Rationale and ObjectiveSirtuin 1 (SIRT1) plays an important role in tumorigenesis and is increased in many human tumors. DBC1 is a negative regulator of SIRT1 via promotion of p53-mediated apoptosis. It is necessary to investigate the expression of SIRT1 and DBC1 in laryngeal and hypopharyngeal squamous cell carcinomas (LSCC and HSCC) and its correlation with available clinical parameters.MethodsThe mRNA levels of SIRT1 and DBC1 were measured in 54 paired LSCC or HSCC tumors and corresponding adjacent noncancerous mucosae using quantitative RT-PCR (qRT-PCR). The protein levels of SIRT1 and DBC1 were also evaluated in 120 cases of patients with LSCC or HSCC using immunohistochemical staining. The correlation between SIRT1 and DBC1 expression and clinical parameters was analyzed with Pearson chi-square test.ResultsqRT-PCR assay showed that, compared with the paired adjacent noncancerous mucosae, SIRT1 mRNA was significantly decreased in tumors. The immunohistochemical results indicated that the SIRT1 protein was also downregulated in tumors compared with noncancerous mucosae. Moreover, decreased SIRT1 was significantly correlated with the tumor clinical stage and lymph node metastasis. Additionally, DBC1 mRNA was significantly increased in tumors compared with noncancerous mucosae. The immunohistochemical results indicated that the DBC1 protein was downregulated in tumors, which is inconsistent with the results obtained by qRT-PCR. Finally, decreased DBC1 protein was significantly correlated with tumor differentiation, lymph node metastasis, and p53 expression.ConclusionsSIRT1 and DBC1 might be involved in the pathophysiology of laryngeal and hypopharyngeal squamous cell carcinomas and are associated with lymph node metastasis and p53 positive staining in LSCCs and HSCCs.