Osteosarcoma is a highly vascular and extremely destructive malignancy, and the survival of patients with osteosarcoma has not improved significantly in recent years. Antiangiogenic therapy currently holds great potential in conjunction with conventional treatment modalities for osteosarcoma. However, there are examples of gradual loss of response, and perhaps acquired resistance to antiangiogenic drugs. The acquired resistance of antiangiogenesis may be associated with a lot of hypoxia-response genes. The human apurinic/apyrimidinic endonuclease (Ape1) protein, a bifunctional redox factor and apurinic/apyrimidinic (AP) endonuclease, plays a crucial role in protecting against cell death due to hypoxia. We therefore hypothesized that Ape1 may contribute to the resistance of antiangiogenic therapy. To investigate the effect of Ape1 on the sensitivity of human osteosarcoma cells to endostatin, we constructed an Ape1 small interfering RNA expression vector, O steosarcoma is the most common malignant bone tumor in children and young people. The peak incidence of osteosarcoma usually occurs in the second and third decade of life, and approximately 1000 new cases a year are diagnosed in the USA. Over the past three decades, advances in treatment have been responsible for improved limb salvage, reduced metastases, and overall higher survival rates.(1) Multiagent doseintensive chemotherapy regimens have resulted in long-term disease-free survival rates of ~60-76% in patients with localized disease.(2) Osteosarcoma patients whose tumors respond poorly to chemotherapy are at a higher risk of relapse and adverse outcome due to the genetic instability and intrinsic concomitant tumor resistance.(3) Angiogenesis inhibitors are new anticancer drugs considered potentially capable of circumventing or significantly delaying acquired drug resistance, because they target the normal -and hence genetically stable -host endothelial cells of a tumor's growing vasculature.(4,5) However, there are examples of gradual loss of response, and perhaps acquired resistance to antiangiogenic drugs or treatment strategies, especially when the drugs are administered as monotherapies. (6) These experiments demonstrate that the genetic background of a tumor cell, in this case the presence or absence of wild-type p53, may be an important determinant of response to antiangiogenic therapy.(7) The acquired resistance to antiangiogenic therapy may be associated with a lot of hypoxia-response genes.(8,9) The human apurinic/apyrimidinic endonuclease (Ape1), a bifunctional redox factor/apurinic/apyrimidinic (AP) endonuclease, plays a crucial role in protecting against cell death due to hypoxia.(10) We therefore hypothesized that Ape1 may contribute to the resistance to antiangiogenic therapy, and the knockdown of Ape1 may enhance tumor sensitivity to antiangiogenic therapy.In the present study, we constructed the specific Ape1 small interfering RNA (siRNA) stable expression vector pSilenceApe1 to knockdown Ape1 expression in the osteosarcoma cells, and to de...
Lung cancer is the leading cause of cancer-related death worldwide. Non-small-cell lung cancer (NSCLC) is the most common pathological type of lung cancer, divided into squamous cell carcinoma and adenocarcinoma. Despite better techniques of surgery and improvement in adjuvant and neoadjuvant therapy, the median survival of advanced NSCLC is only 8-10 months. With increased understanding of molecular alternations in NSCLC, considerable efforts have focused on the development of personalized molecular-targeted therapies. The PI3K/AKT/mTOR pathway regulates tumor development, growth, and proliferation of NSCLC. Various novel inhibitors targeting this pathway have been identified in preclinical studies or clinical trials. Some genetic alternations may be considered sensitive or resistant biomarkers to these inhibitors. Sometimes, upregulation of RTK and the downstream PI3K pathway or upregulation of the ERK pathway by compensatory feedback reactivation in response to these inhibitors also lead to drug resistance. Therefore, combination therapy of these inhibitors and other targeted inhibitors such as EGFR-TKI or MEK inhibitors according to genetic status and categories of inhibitors is required to enhance the efficacy of these inhibitors. Here, we reviewed the genetic status of the PI3K/AKT/mTOR pathway in NSCLC and the novel inhibitors targeting this pathway in preclinical or clinical studies, exploring the possible genetic alternations related to different inhibitors and the means to enhance the antitumor effect in NSCLC.
Here, we aimed to investigate the carcinogenic effects of apolipoprotein C1 (APOC1) in prostate cancer (PCa). APOC1 expression was evaluated in PCa and normal prostate specimens, and lentivirus‐mediated RNA interference was used to knockdown APOC1 in DU145 cells. The effects of APOC1 silencing on cell proliferation, cell cycle arrest, and apoptosis were assessed. APOC1 expression was much higher in PCa tissues than in normal tissues. Moreover, APOC1 silencing inhibited cell proliferation and colony formation, arrested cell cycle progression, and enhanced apoptosis in DU145 cells. Additionally, APOC1 silencing decreased survivin, phospho‐Rb, and p21 levels and increased cleaved caspase‐3 expression. These data supported the procarcinogenic effects of APOC1 in the pathogenesis of PCa and suggested that targeting APOC1 may have applications in the treatment of PCa.
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