ABSTRACT
The authors wish to make the following correction to their published paper [...].
ABSTRACT
The use of a mixture of amino acids caused a selective apoptosis induction against a variety of tumor cell lines, reduced the adverse effects of anti-cancer drugs and increased the sensitivity of tumor cells to chemotherapeutic agents. We evaluated the effects and underlying mechanisms of soy-derived multiple amino acids' oral supplementation on the therapeutic efficacy of low-dose cyclophosphamide (CTX) and on tumor growth, apoptosis, and autophagy in severe combined immunodeficiency (SCID) mice that were injected with sarcoma-180 (S-180) cells. 3-methyladenine or siRNA knockdown of Atg5 was used to evaluate its effect on sarcoma growth. A comparison of mice with implanted sarcoma cells, CTX, and oral saline and mice with implanted sarcoma cells, CTX, and an oral soy-derived multiple amino acid supplement indicated that the soy-derived multiple amino acid supplement significantly decreased overall sarcoma growth, increased the Bax/Bcl-2 ratio, caspase 3 expression, and apoptosis, and depressed LC3 II-mediated autophagy. Treatment with 3-methyladenine or Atg5 siRNA elicited similar responses as CTX plus soy-derived multiple amino acid in downregulating autophagy and upregulating apoptosis. A low dose of CTX combined with an oral soy-derived multiple amino acid supplement had a potent anti-tumor effect mediated through downregulation of autophagy and upregulation of apoptosis.
Subject(s)
Amino Acids/pharmacology , Cyclophosphamide/therapeutic use , Dietary Supplements , Glycine max/chemistry , Neoplasms, Experimental/drug therapy , Sarcoma/drug therapy , Administration, Oral , Amino Acids/administration & dosage , Amino Acids/chemistry , Animals , Antineoplastic Agents, Alkylating/administration & dosage , Antineoplastic Agents, Alkylating/pharmacokinetics , Antineoplastic Agents, Alkylating/therapeutic use , Cyclophosphamide/administration & dosage , Cyclophosphamide/pharmacokinetics , Dose-Response Relationship, Drug , Drug Synergism , Gene Expression Regulation, Neoplastic/drug effects , Humans , Male , Mice , Mice, SCID , Mitochondria/drug effectsABSTRACT
AIMS: Repetitive hypoxic preconditioning (RHP) may provide more efficient protection than single hypoxic preconditioning against renal ischemia/reperfusion-induced injury via hypoxia-induced factor 1alpha (HIF-1alpha)-dependent heat shock protein 70 (HSP70) pathways. MAIN METHODS: Wistar rats were subjected to intermittent hypoxic exposure (15h/day), whereas controls were kept at sea level. We evaluated renal expression of HIF-1alpha, HSP70, the endoplasmic reticulum stress protein GRP78, caspase 12, Beclin-1, and poly-(ADP-ribose)-polymerase (PARP) with western blotting. Renal apoptosis determined by terminal transferase dUTP nick end labeling (TUNEL), Beclin-1-dependent autophagy, and monocyte/macrophage (ED-1) infiltration were evaluated by immunocytochemistry. Renal function was determined with blood urea nitrogen (BUN) and plasma creatinine levels. HIF-1alpha inhibitors and Deoxyribonucleotide (DNA) or Ribonucleotide (RNA) interference of HSP70 were used to evaluate their possible roles in this process. KEY FINDINGS: Renal HIF-1alpha and HSP70 expression were enhanced by hypoxic preconditioning and inhibited by the HIF-1alpha inhibitor, YC-1, as well as phosphatidylinositol 3-kinase (PI3K)/Akt inhibitors. After the return to normoxia, renal HSP70 protein levels were maintained for one week in the RHP group, but they decayed after one day in the single hypoxic preconditioning group. Ischemia/reperfusion significantly increased renal TUNEL-apoptosis, Beclin-1-dependent autophagy, ED-1 infiltration, expression of GRP78, caspase 12, Beclin-1, PARP, and BUN and plasma creatinine levels in control rats. RHP significantly decreased all ischemia/reperfusion-enhanced parameters. Intraperitoneal pretreatment with YC-1 and quercetin (an inhibitor of HSP70 induction) eliminated RHP-induced protection. Anti-sense oligodeoxyribonucleotides or interference RNA targeting HSP70 abrogated the protection against hypoxia/reoxygenation-induced oxidative injury in RHP-treated proximal tubules. SIGNIFICANCE: We demonstrate that RHP promotes HIF-1alpha-dependent HSP70 signaling to reduce renal ischemia/reperfusion injury.