Therapeutics by cytotoxic metabolite accumulation: pemetrexed causes ZMP accumulation, AMPK activation, and mammalian target of rapamycin inhibition.
Pemetrexed represents the first antifolate cancer drug to be approved by the Food and Drug Administration in 20 years; it is currently in widespread use for first line therapy of mesothelioma and non-small cell lung cancer. Pemetrexed has more than one site of action; the primary site is thymidylate synthase. We now report that the secondary target is the downstream folate-dependent enzyme in de novo purine synthesis, aminoimidazolecarboxamide ribonucleotide formyltransferase (AICART). The substrate of the AICART reaction, ZMP, accumulated in intact pemetrexed-inhibited tumor cells, identifying AICART as the step in purine synthesis that becomes rate-limiting after drug treatment. The accumulating ZMP causes an activation of AMP-activated protein kinase with subsequent inhibition of the mammalian target of rapamycin (mTOR) and hypophosphorylation of the downstream targets of mTOR that control initiation of protein synthesis and cell growth. We suggest that the activity of pemetrexed against human cancers is a reflection of its direct inhibition of folate-dependent target proteins combined with prolonged inhibition of the mTOR pathway secondary to accumulation of ZMP.
Racanelli
Alexandra C
AC
Department of Pharmacology and the Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia 23298-0035, USA.
Rothbart
Scott B
SB
Heyer
Cortney L
CL
Moran
Richard G
RG
D000263:Adenylate Kinase / Q000187:drug effects / Q000378:metabolism*; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005493:Folic Acid Antagonists / Q000627:therapeutic use*; D005971:Glutamates / Q000627:therapeutic use*; D005998:Glycine / Q000031:analogs & derivatives / Q000096:biosynthesis / Q000378:metabolism; D006147:Guanine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006801:Humans; D007700:Kinetics; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology; D008654:Mesothelioma / Q000188:drug therapy* / Q000473:pathology; D000068437:Pemetrexed; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000473:pathology; D011494:Protein Kinases / Q000187:drug effects / Q000378:metabolism*; D012265:Ribonucleotides / Q000096:biosynthesis / Q000378:metabolism* / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases
D000970:Antineoplastic Agents; D005493:Folic Acid Antagonists; D005971:Glutamates; D012265:Ribonucleotides; D000068437:Pemetrexed; C002824:phosphoribosyl-N-formylglycineamide; D000620:Aminoimidazole Carboxamide; D006147:Guanine; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D000263:Adenylate Kinase; C031143:AICA ribonucleotide; D005998:Glycine