Advances in antitumor effects of NSAIDs

Figures & data

Table 1 Aspirin use for the primary prevention of cardiovascular disease and colorectal cancer in the USA: clinical summary¹⁹

Population	Recommendation	Recommended instructions	Treatment and dosage	Balance of benefits and harms	Risk assessment
Adults younger than 50 years	No recommendation. grade:I	The current evidence is insufficient to assess the balance of benefits and harms of initiating aspirin use for the primary prevention of CVD and CRC in adults younger than 50 years	A reasonable approach consistent with the evidence is to prescribe 81 mg/d (the most commonly prescribed dose in the USA), and assess CVD and bleeding risk factors starting at age 50 y and periodically thereafter, as well as when CVD and bleeding risk factors are first detected or change.	The benefits of aspirin use outweigh the increased risk for bleeding by a moderate amount.	Primary risk factors for CVD are older age, male sex, race/ ethnicity, abnormal lipid levels, high blood pressure, diabetes, and smoking. Risk factors for GI bleeding with aspirin use include higher aspirin dose and longer duration of use, history of GI ulcers or upper GI pain, bleeding disorders, renal failure severe liver disease, and thrombocytopenia.
Adults aged 50–59 years with a≥10% 10-years CVD risk	Initiate low-dose aspirin use. Grade:B	Persons who are not at increased risk for bleeding, have a life expectancy of at least 10 years, and are willing to take low-dose aspirin daily for at least 10 years		The benefits of aspirin use outweigh the increased risk for bleeding by a small amount.
Adults aged 60–69 years with a ≥10% 10-years CVD risk	The decision to initiate low-aspirin use is an individual one. Grade:C	Persons who are not at increased risk for bleeding, have a life expectancy of at least 10 years, and are willing to take low-dose aspirin daily for at least 10 years are more likely to benefit. Persons who place a higher value on the potential benefits than the potential harms may choose to initiate low-dose aspirin. (C recommendation)		The evidence on aspirin use is insufficient and the balance of benefits and harms cannot be determined.
Adults aged 70 years or older	No recommendation. grade:I	The current evidence is insufficient to assess the balance of benefits and harms of initiating aspirin use for the primary prevention of CVD and CRC in adults aged 70 years or older.		The evidence on aspirin use is insufficient and the balance of benefits and harms cannot be determined.

Abbreviations: CVD, cardiovascular disease; CRC, colorectal cancer; GI, gastrointestinal.

Table 2 Traditional pathway of NSAIDs inhibiting tumors

NSAIDs	Target	Pathway	Result
Aspirin	Downregulate COX-2 expression^Citation26,Citation28	Downregulation of bcl-2 expression Downregulation of mmp-2 expression	Cell apoptosis Reduce tumor cell invasion
Aspirin/naproxen	Downregulation of bcl-2 expression and up-regulation of bax expression^Citation33^–^Citation35	Caspase cascade reaction	Cell apoptosis
Sulindac acid	Degrade antiapoptotic protein bcl-XL^Citation36	Pro-apoptotic protein bax activation caspase cascade reaction	Cell apoptosis
Amino salicylic acid	Increase reactive oxygen species^Citation37	The mitochondrial permeability changes; bcl-2 expression down regulated	Cell apoptosis
Celecoxib	Increase p53 gene expression^Citation38	Upregulation of PUMA and BH3-only expression	Cell apoptosis by the p53 pathway
Aspirin	Upregulation of hMLH1, hMSH2, hMSH6 and hPMS2 expression^Citation44 Upregulation of XRCC3 expression^Citation45		Promote DNA self-healing

Abbreviations: COX-2, cyclooxygenase-2; NSAIDs, nonsteroidal anti-inflammatory drugs; XRCC3, X-ray repair of cross-complementary gene 3.

Table 3 The new thinking about NSAIDs inhibiting tumors

NSAIDs	Target	Target function	Interaction
Aspirin	PGE2^Citation48	Attenuate the immune system’s normal response to diseased cells and help cancer cells to hide	Inhibit the synthesis of PGE2
Aspirin	Platelets^Citation49,Citation52^–^Citation54	In vivo platelet-derived or non-platelet-derived TGFβ and GARP complex can effectively reduce the activity of T-cell activity Platelets spontaneously recruited help the tumor growth, enhance the invasiveness, promote EMT transformation	Inhibit the activity of COX-1 enzyme, control the number of circulating platelets and their activity levels
Aspirin	Genetic mutations^Citation56	Tumorigenesis is caused by long-term accumulation of genetic mutations	Slow down gene mutation accumulation and protect normal cell DNA
	DNA damage^Citation42,Citation57	Gene damage increases the chance of DNA sequence changes
Aspirin/ Indomethacin	Traditional chemotherapy drugs therapy^Citation62^–^Citation64	Direct killing of tumor cells by multiple ways	Increase drug toxicity and downregulate cellular drug resistance
	Adoptive T-cell therapy^Citation49	Organism’s own T cells are propagated in vitro and chosen specifically to recognize tumor cells. The culture is expanded and then returned to the cancer patients	Attenuate the ability of platelets to help tumor cells escape immune clearance

Abbrevations: GARP, Glycoprotein A Repetitions Predominant; NSAIDs, nonsteroidal anti-inflammatory drugs; PGE2, prostaglandin E2.

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