COX-2 INHIBITORS IN HUMAN CANCER PREVENTION

THE ROLE OF COX-2 INHIBITORS IN HUMAN CANCER PREVENTION AND OTHER NOVEL TARGETS - A RECENT REVIEW

Authors: 
Lohithasu Duppala¹, Madhu priya Damuluri¹, Anil kumar vadda²

ABSTRACT:
COX-2 (Cyclooxygenase-2) is a selective inhibitor of non-steroidal anti-inflammatory drug (NSAID). Cyclooxygenase -2, an enzyme responsible for inflammation and pain. Celecoxib, Rofecoxib, valdecoxib, Parecoxib are class of COX-2 inhibiting drugs. COX-2  inhibitors have been revealed to reduce the occurrence of cancers and pre-cancerous growths. Celecoxib, cox-2 inhibitor isused to prevention of polyp formation in Familial Adenomatous Polyposis (FAP). COX-2 inhibitors like celecoxib, Rofecoxib, valdecoxib, Parecoxibare currently being studied in  cancer treatment and other targets. This review highlights the COX-2 inhibitors with special emphasis on their role in various kinds of cancer prevention and other targeted therapy. COX-2inhibitors in cancer chemotherapy and neurological diseases like Parkinson and Alzheimer’s diseases still continues to attract researches on the development of COX-2 inhibitors.

INTRODUCTION:
Cancer is an unregulated cell growth,forming malignant tumors, and invade nearby organs of the body. The cancer may also spread  to more far-away parts of the body through the lymphatic system or blood. Cancer may be caused by Chemicals, Diet and exercise, Infections, Radiation, heredity, physical agents, hormonal imbalance etc., Now-a-days, the most effective treatments for cancer, including a variety of combinations of surgical resection, radiation, chemotherapy, depend on the detection of cancer at a very early-stage. ^1,2

Cyclo-oxygenases (COXs) are rate-limiting enzymes in arachidonic acid metabolism and prostaglandin production. There are two forms of COX--COX-1 and COX-2-and they differ in various respects.

CLASSIFICATION:
On the basis of source, action, mechanisms, the drugs are also classified as:

• Alkylating agents,

• Antimetabolites,

• Natural products,

• Hormones and antagonists

• Miscellaneous agents-COX-2 inhibitors

COX-1 can be expressed, in most tissues in the body and mediates the production of prostaglandins that control common physiological functions, together with the maintenance of the gastric mucosa and renal blood flow.

COX-2 is absent in most normal tissues.

These are  inducible expression,

These are  present in inflammatory, neoplatic sites, kidney,  uterus, ovary, brain and small intestine.

COX-2 regulated the -

• Pathologic- Information, Pain, Fever, Dysregulated proliferation
• Tissue Repair, cancer treatment
• Physiologic- Reproduction .Renal functions
• Development-  kidney

ADVANTAGES:

• Similar in effectiveness as Non-selective NSAIDS ,

• Less gastric ulcerations, GI symptoms still occur but less,

• Less serious GI events-perforations, bleeds than nonselective therapies,

• No effect on platelet function.

• COX mediatedoxidation is essential in the calcium-dependentglutamate signaling pathway that involves N-methyl CDaspartate,

• COX-2 inhibitors may be able to protectneurons directly by reducing cellular response toglutamate and have potential to reduce the risk ofAlzheimer’s disease,

• NSAID’s may manipulate inflammation byinhibiting COX-1 and COX-2 and by activating theperoxisome proliferators nucleartranscription factor,

LIMITATIONS:

• Increased risk of myocardial infarction, stroke

• Efficacy, safety, cost and administration (vomiting sensation) etc.,

THE ROLE OF COX-2 INHIBITORS :

COX-2  INHIBITION IN BREAST CANCER:
Cyclo-oxygenase-2 (COX-2) is overexpressed in several epithelial tumours, including breast cancer.COX inhibition in breast cancer could have two main roles^3,4:
(i) primary prevention  included that to prevent onset of the disease in patients at elevated risk

(ii) secondary prevention included that in treatment of established breast cancer with  COX-2 inhibitors to reduce ferociousnessand induce remission.

Cyclo-oxygenase-2 indirectly affects mutagenesis, angiogenesis, enhanced cell migration and apoptosis.  Celecoxib has been revealed to inhibit proliferation of human breast cancer cell lines.⁵Combination therapy with aromatase inhibitors (AIs) and celecoxib has better efficacy and safety for the treatment of patients with metastatic breast cancer than monotherapy.

COX-2  INHIBITION IN METACHRONOUS GASTRIC  CANCER:
Selective inhibition of COX-2 prevented the progression of premalignant gastric lesions ⁶ and the development of gastric cancer in H. pylori–infected Mongolian gerbils^7,8 Treatment with COX-2 inhibitors thus appears tohave benefi cial preventive effects on H. Pylori -associatedstomach carcinogenesi The role of infection withHelicobacterpylori in the development of gastric cancer is controversial. Its classifi cation as a class 1 carcinogen suggestsit may play an important role in the origin of gastriccancer. H. pylori is thought to prompt chronic infl ammationof the infected gastric mucosa, which is considereda major risk factor for gastric cancer and associated precursor lesions.Selective cyclooxygenase (COX)-2 inhibitors (coxibs) were originally developed as one of anti-inflammatory drugs to avoid side effect of NSAIDs.