LAUSR

Atorvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, is known to be of significant benefit in the treatment of hyperlipidemias. In addition, statins have the ability to attenuate matrix metalloprotease activity, reduce inflammatory response, restore antioxidant defenses, and reduce endoplasmic reticulum stress.1,2 Some of these beneficial actions of statins seem to be brought about by their ability to upregulate Nrf2 expression and stimulate Nrf2 nuclear translocation, induce antioxidant enzymes (HO-1, NQO1, and GCLC), and modulate PI3K/Akt/ERK pathway.3,4 It was reported that simvastatin markedly suppressed PI3K/Akt/mTOR signaling by activating PTEN and by dephosphorylating Akt and S6RP (P = 0.033); it also inhibited MAPK/ERK pathway by dephosphorylating c-Raf and ERK1/2. These results suggest that statins may have cytoprotective action. This is supported by the observation that doxorubicin can cause glomerulosclerosis by enhancing the expression of NF-kB, IL-1b, and TGF-b inflammation and simvastatin suppressed these expressions and, thus, seems to bring about its nephroprotective action.5 It is noteworthy that simvastatin directly inhibits ATP-binding cassette transporters such as ABCB1 (P-glycoprotein), an important mechanism of multidrug resistance in cancer therapy, and, thus, brings about its (simvastatin) anticancer action and also potentiated (especially lovastatin) apoptosis of cancer cells induced by conventional anticancer drugs.6–8 In this context, it is interesting to note that atorvastatin can protect cardiac tissue from the cytotoxic action of doxorubicin.9 These interesting results open a new window of opportunity to protect cardiac toxicity induced by doxorubicin. But, obviously more studies are needed to extrapolate these results to humans. Most important of all is to find out whether all statins have similar cardioprotective action against doxorubicin. Based on these results, it remains to be studied whether statins possess differential action on normal and tumor cells, wherein normal cells (such as cardiac and renal) are protected from the cytotoxic action of doxorubicin and simultaneously are able to show anticancer action and potentiate the tumoricidal action of anticancer drugs. Such an action of statins, if proved to be true, it would certainly be a boon to cancer patients and enhance the armamentarium of physicians in their fight against cancer. It is also not certain whether such differential action of statins on normal and tumor cells is possessed by all statins or is restricted to certain statins only. Previously, I proposed that statins may bring about some of their beneficial actions by modulating the metabolism of essential fatty acids (EFAs).10 This proposal has since been supported by several other studies.11–15 It was reported that statins enhance dietary linoleic acid (LA, 18:2 n-6) and possibly that of a-linolenic acid (ALA, 18:3 n-3) metabolism and enhance the formation of their long-chain metabolites such as g-linolenic acid (GLA, 18:3 n-6), dihomo-GLA (DGLA, 20:3 n-6), arachidonic acid (from LA), eicosapentaenoic acid (EPA, 20:5 n-3), and docosahexaenoic acid (DHA, 22:6 n-3) (from ALA). Statins seem to enhance specifically the formation of AA by augmenting the activity of Δ5 desaturase compared with all other fatty acids14,16–21 and its (AA) conversion to prostacyclin and lipoxin A4 (LXA4) and increase the production of nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S) that are potent platelet antiaggregators and vasodilators.17,22–26 All these polyunsaturated fatty acids (PUFAs such as GLA, DGLA, AA, EPA,