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

About Authors:
Lohithasu Duppala^*1, Madhu priya Damuluri¹, Anil kumar vadda^2

1GITAM Institute of Pharmacy, GITAM University, Pharmaceutics, visakhapatnam, Andhra Pradesh, India-530045.²AVANTHI Institute of pharmaceutical sciences, pharmacology, visakhapatnam, Andhra Pradesh, India-530045.^*lohithasu@gmail.com, anilkumar.vadda@gmail.com

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-2 inhibitors in cancer chemotherapy and neurological diseases like Parkinson and Alzheimer’s diseases still continues to attract researches on the development of COX-2 inhibitors.

REFERENCE ID: PHARMATUTOR-ART-1647

INTRODUCTION:
Canceris a 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-1can 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 with Helicobacterpylori 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.

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COX-2 INHIBITION IN OVARIAN CARCINOMA:
COX-2 is an immediate-early gene and is induced by different stimuli including mitogens, cytokines, growth factors and tumor inducers. Improved expression of COX-2 has been related to inflammatory processes and Carcinogenesis.^9,10.The expression of COX-2 is elevated in ovarian cancer.^11,12 COX-2 specific inhibitors may play an important role in regulating tumor tissue angiogenesis.

COX-2 INHIBITION IN COLORECTAL CARCINOMA(CRC):
Non-steroidal anti-inflammatory drugs (NSAIDs) for the prevention and adjuvant therapy of colorectal cancer.COX-2 is frequently over expressed in colonic adenomas and carcinomas¹³.Colorectal cancer (CRC) is a heterogeneous disease. Three major forms of CRC have been described:1. hereditary, 2.sporadic, and 3.colitis-associated CRC. Compounds found to decrease the risk of CRC includes non-selective nonsteroidal anti-inflammatory drugs (NSAIDs), which target the cyclooxygenase enzymes (COX-1 and COX-2).Selective COX-2 inhibitors (COXIBs) such as celecoxib, rofecoxib, and valdecoxib in order to overcome the gastrointestinal adverse events of nonselective NSAIDs that placed limits on effective therapy.In particularly, aspirin specifically prevents the subgroup of patients whose colon tumors expressed COX-2 at higher levels .

COX-2 INHIBITION INHEPATOCELLULAR CARCINOMA:
The role of COX-2 in hepatocellular carcinogenesis is less clear. It has been recognized that colorectal cancer, metastatic to the liver, expressed by COX-2. Also, some previous reports indicate that COX-2 levels are elevated in some hepatocellular carcinomas^14,15,16Celecoxib retards the growth of lung tumors and decreases the number and size of metastases. Adding COX-2 to chemotherapy provides an additive effect.

OTHER TARGETS :
NEUROPSYCHIATRIC DISORDERS:
COX-2 inhibitors like celecoxib, ,Rofecoxib have been found to be effective in suppressing inflammatory neurodegenerative pathways in mental illness, with positive results in trials for major depressive disorder as well as schizophrenia.

THE ANTI-INFLAMMATORY AND ANALGESIC:
The inhibition of COX-2 for the anti-inflammatory and analgesic function of the selective COX-2 inhibitor celecoxib and also for its ability to prevent the development of cancerous growth. , a recent study with various malignant tumor cells showed that celecoxib could inhibit the growth of these cells, even though some of these cancer cells didn’t even contain COX-2.

ANTITUMOR EFFECTS INDUCED BY COX-2 INHIBITOR IN URINARY BLADDER CANCER CELLS:
Urinary bladder cancer is a common malignancy tumours.The highest incidence of reported bladder cancer occurs in industrialized countries and areas . COX-2 is an inducible isoform of CycloOXygenase, the enzyme that catalyzes the rate-limiting step in the synthesis of prostaglandins from arachidonic acid. It has been reported that normal human urinary bladder epithelium does not express COX-2, but that COX-2 is overexpressed in nearly 85% of invasive TCCs and 75% of specimens from carcinoma in situ of the urinary bladder (8). reports of overexpression of COX-2 in various cancers, there is also evidence that COX-2 actively participates in the process of carcinogenesis and cancer progression ; that is, COX-2 is more than a by stander. COX-2 expression has been linked to imparting resistance to induction of apoptosis, suppressing the host immune system, enhancing cancer cell growth and invasion, and promoting angiogenesis.^17,18

TREATMENT OF OESOPHAGEAL ADENOCARCINOMA:
COX-2 is not usually detectable in normal tissues, but can be readily induced in processes like inflammation, reproduction and carcinogenesis. The mechanisms by which COX-2 is thought to be involved in the carcinogenesis include resisting apoptosis, increasing cell proliferation, stimulating angiogenesis and modulating the invasive properties of cancer cells.

NEW DIRECTION STUDIES OF COX-2 INHIBITORS:
COX-2 is the main UV-responsive COX isoform in human skin and is involved in UV-induced skin inflammation and apoptosis.COX-2 inhibitors are likely to be used increasingly for the treatment of pain and inflammation, and several other COX-2 inhibitors are currently under development. Future industry-independent analysis of published and unpublished data will reduce potential bias error. The Baltimore Longitudinal Study of Aging reported that the risk of developing Alzheimer’s disease was reduced among NSAID users, especially in those who had taken the medications for 2 yr or more¹⁹. Other studies have confirmed this association ^20,21. A possible mechanism for this effect is a reduction in inflammatoryprocesses that may promote neuronal destruction. The use of COX-2-selective drugs to decrease the risk of Alzheimer’s disease is being studied. Studies are also continuing to assess the use of COX inhibitors in the treatment of colorectal cancer, esophageal cancer ²², gastric cancer, and breast cancer ^23,24. They represent a significant therapeutic development because of their improved side effect profile compared with conventional NSAIDs . The use of COX-2 inhibitors, such as restriction of their use to patients at increased risk for complications, cost-effectiveness, safety compared with conventional NSAIDs plus prostaglandin replacement or acid-reduction therapy, and safety in patients also taking aspirin for platelet inhibition ^25,26.

Epidemiological studies have exposed that the use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with a reduced risk of numerous malignancies, including colorectal cancer.

PRINCIPLES OF COMBINATION THERAPIES:
1.Select drugs according to their phase specific characteristics,
2.Combinations of antineoplastic drugs with different action mechanisms,
3.Combinations of antineoplastic drugs with other therapies,
4.Combination of low-toxic drugs with hightoxic ones,
5.Select drugs according to antineoplastic range (spectrum).
6. Use right dose

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