COX-2 and its inhibition as a molecular target in the prevention and treatment of lung cancer

Abstract

Lung cancer is the leading cause of cancer death in the USA. Conventional therapy using chemotherapy, radiation therapy, and a combination of the two, has yielded modest improvement in patient outcome. Dysfunction and dysregulation of many molecular processes and signaling pathways are involved in the development and growth of malignant lung tumors, and in conferring resistance to standard cancer treatments. Cyclooxygenase (COX)-2, an enzyme involved in prostaglandin production in pathologic states, is often overexpressed in premalignant and malignant lesions. Overexpression of COX-2 in lung cancer is associated with more aggressive biologic tumor behavior and adverse patient outcome. In preclinical studies, inhibition of this enzyme with selective COX-2 inhibitors enhances tumor response to radiation and chemotherapeutic agents. These findings quickly led to clinical studies. Phase I and II clinical trials of the combination of selective COX-2 inhibitors with radiotherapy, chemotherapy, or both in patients with lung cancer have been initiated and some preliminary results are available. In this review, the relationship between overexpression of COX-2 and lung cancer, the antitumor effect of selective COX-2 inhibitors, and the rationale for using selective COX-2 inhibitors combined with radiotherapy and chemotherapy, will be described. Current clinical protocols and preliminary findings will also be summarized.

Constitutive activation of the CD40 pathway promotes cell transformation and neoplastic growth

“…A role for CD40 in inflammation is highlighted by the observation that CD40 engagement induces the synthesis of the proinflammatory cyclooxygenase-2 (COX-2)/prostaglandin E2 system in lung fibroblasts and disruption of the constitutive CD40-CD40L pathway reduces lung inflammation and fibrosis (Adawi et al, 1998;Zhang et al, 1998). Similarly, COX-2 inhibitors confer therapeutic benefits for the treatment of lung cancer (reviewed by Liao and Milas, 2004). A recent report has demonstrated that NF-kB is a critical link between inflammation and cancer, promoting the conversion of chronic inflammatory liver disease to hepatocellular carcinoma in a mouse model (Pikarsky et al, 2004).…”

What are cyclooxygenases and lipoxygenases doing in the driver's seat of carcinogenesis?

“…This suggests that an adjuvant treatment with COX inhibitors may increase the therapeutic efficiency of distinct chemotherapeutic agents and radiation. 87 5-or 12-LOX inhibitors were reported to induce apoptosis in human breast, gastric, hepatocellular, pancreatic and prostate cancer cells. 35,36 In human breast cancer cells, both 5-LOX and 12-LOX inhibitors induce apoptosis through cytochrome c release and caspase 9 activation whereas 5-HETE and 12-HETE stimulate proliferation of this cells.…”

Prostaglandin E2 Impairs CD4+ T Cell Activation by Inhibition of lck: Implications in Hodgkin's Lymphoma

“…Selective COX-2 inhibitors are tested in clinical trials for prevention and tumor therapy (47)(48)(49) and preclinical data suggests that COX-2 inhibitors might act additively or synergistically with the specific chemotherapeutic agents used in the treatment of these tumors.…”