High-dose erlotinib is effective for non-small cell lung cancer patients with brain metastases. The aim of the present study was to investigate whether aspirin could increase the anti-proliferative and anti-metastatic effects of regular erlotinib treatment. The data demonstrated that combining aspirin with erlotinib significantly induced apoptosis and inhibited tumor cell proliferation in several human cancer types. Furthermore, aspirin plus erlotinib significantly induced the activation of E-cadherin and suppression of p38. The data also indicated that the p38/E-cadherin pathway may be involved in the apoptosis caused by the combination of aspirin and erlotinib. As p38 and E-cadherin also serve a key role in epithelial-to-mesenchymal transition (EMT) and cancer metastasis, we hypothesized that the combination of aspirin and erlotinib may significantly inhibit tumor metastasis. First, aspirin plus erlotinib achieved potent inhibition of cancer cell migration and invasion, which are crucial for cancer metastasis. Next, the results demonstrated that aspirin plus erlotinib inhibited angiogenesis by suppressing endothelial cell migration and invasion. Moreover, it was confirmed that aspirin plus erlotinib exerted synergistic anti-angiogenic effects. Finally, the synergistic anti-proliferative and anti-metastatic effects of the combination of aspirin with erlotinib were further validated in an A549 xenograft model . In conclusion, aspirin plus erlotinib may be an effective combination regimen for patients with metastatic cancer.

The quantification of intracranial gefitinib (GEF) exposure is limited owing to the sensitivity of analytical equipment. Although mass spectrometry (MS) is the preferred method because of its high sensitivity, the equipment is not available in many laboratories, especially in developing Asian countries. In this paper, we developed a highly sensitive high performance liquid chromatography-diode array detector (HPLC-DAD) method for the assay of GEF in human cerebrospinal fluid (CSF) and plasma. GEF was extracted from CSF and plasma by solid-phase extraction and liquid-liquid extraction, respectively. The chromatographic separation was performed on a C18 column with gradient elution of 0.1% triethylamine solution and acetonitrile, then finally detected at 344 nm. This method was validated and proved to be highly sensitive with a lower limit of quantitation value of 0.11 ng/mL in CSF and 11 ng/mL in plasma. The blood-brain barrier penetration ratio of GEF ranged from 1.48 to 2.41%. This method provides a reliable MS-independent solution for the quantitation of GEF in patients' CSF and plasma.

Abstract. Platinum compounds, such as cisplatin, carboplatin, oxaliplatin and nedaplatin, are widely used to treat a number of solid malignancies. Nedaplatin is a second-generation platinum complex, based on its pronounced anti-cancer activities against several solid tumors being equivalent to that of cisplatin, but with lower nephrotoxicity. In this context, the present study aimed to investigate the potential anti-cancer effect by combining nedaplatin with ABT-737. It was found that nedaplatin greatly increased ABT-737-mediated apoptosis in A549 and 95-D cells, accompanied by enhanced cleavage of poly(ADP-ribose) polymerase and caspase-3. In addition, this enhancement was also paralleled by cytochrome c release and dissipation of mitochondrial membrane potential. Additional mechanistic investigations revealed that nedaplatin plus ABT-737 exerted a synergistic effect on cancer cells through their ability to accelerate the degradation of Mcl-1. The present study has revealed nedaplatin as a pertinent sensitizer to ABT-737, which opens up new avenues for this promising BH3-mimetic molecule in the clinic. IntroductionNedaplatin, a platinum derivative synthesized to overcome problems of cisplatin resistance, was developed by Shionogi Pharmaceutical Company in 1983 with the aim to provide a treatment with effectiveness similar to cisplatin, but with less nephrotoxicity and gastrointestinal toxicities (1). Nedaplatin produces promising response rates in clinical trials as a monotherapy for the treatment of squamous cell carcinoma of the uterus, cervix, head and neck, ovary, lung and esophagus (2-4). Nedaplatin exerts anti-tumor effects following uptake into tumor cells by binding to DNA bases and inhibiting DNA replication, similar to cisplatin and carboplatin (5). However, the ability of cancer cells to become resistant to nedaplatin remains a notable obstacle to successful chemotherapy; resistance of numerous species of cancer cells to nedaplatin can be reversed by combining with chemotherapeutic agents, including 5-fluorouracil, docetaxel and vindesine (6-8). The identification of new chemotherapy regimens incorporating nedaplatin with other chemotherapeutic agents can enhance the knowledge of nedaplatin resistance and support the development of nedaplatin-based approaches to cancer therapy.The B-cell lymphoma 2 (Bcl-2) family members serve as primary regulators of apoptosis and include both pro-and anti-apoptotic molecules (9). Overexpression of anti-apoptotic Bcl-2 family proteins has been associated with chemotherapy resistance in multiple human cancers (10). Myeloid cell leukemia 1 (Mcl-1), an anti-apoptotic protein in the Bcl-2 family, is frequently observed in numerous tumor types and contributes to chemotherapeutic resistance (11).ABT-737 is a small molecule inhibitor of Bcl-2 family proteins. It can bind Bcl-2 and B-cell lymphoma-extra large (Bcl-xL) with high affinity. ABT-737 has shown single agent and combination therapy efficacy against multiple myeloma, acute myeloid leukemia, lymphoma and solid tumor...