Enhancement of 5-FU sensitivity by the proapoptotic rpL3 gene in p53 null colon cancer cells through combined polymer nanoparticles.
Colon cancer is one of the leading causes of cancer-related death worldwide and the therapy with 5-fluorouracil (5-FU) is mainly limited due to resistance. Recently, we have demonstrated that nucleolar stress upon 5-FU treatment leads to the activation of ribosome-free rpL3 (L3) as proapoptotic factor. In this study, we analyzed L3 expression profile in colon cancer tissues and demonstrated that L3 mRNA amount decreased with malignant progression and the intensity of its expression was inversely related to tumor grade and Bcl-2/Bax ratio. With the aim to develop a combined therapy of 5-FU plus plasmid encoding L3 (pL3), we firstly assessed the potentiation of the cytotoxic effect of 5-FU on colon cancer cells by L3. Next, 10 μM 5-FU and 2 μg of pL3 were encapsulated in biocompatible nanoparticles (NPs) chemically conjugated with HA to achieve active tumor-targeting ability in CD44 overexpressing cancer cells. We showed the specific intracellular accumulation of NPs in cells and a sustained release for 5-FU and L3. Analysis of cytotoxicity and apoptotic induction potential of combined NPs clearly showed that the 5-FU plus L3 were more effective in inducing apoptosis than 5-FU or L3 alone. Furthermore, we show that the cancer-specific chemosensitizer effect of combined NPs may be dependent on L3 ability to affect 5-FU efflux by controlling P-gp (P-glycoprotein) expression. These results led us to propose a novel combined therapy with the use of 5-FU plus L3 in order to establish individualized therapy by examining L3 profiles in tumors to yield a better clinical outcomes.
Laboratory of Biochemistry, Department of Pharmacy, University of Napoli Federico II, 80131 Napoli, Italy.
Annapina
A
Russo
Laboratory of Drug Delivery, Department of Pharmacy, University of Napoli Federico II, 80131 Napoli, Italy.
Sara
S
Maiolino
Laboratory of Biochemistry, Department of Pharmacy, University of Napoli Federico II, 80131 Napoli, Italy.
Valentina
V
Pagliara
Laboratory of Drug Delivery, Department of Pharmacy, University of Napoli Federico II, 80131 Napoli, Italy.
Francesca
F
Ungaro
Istituto Nazionale Tumori "Fondazione Pascale"-IRCCS, 80131 Napoli, Italy.
Fabiana
F
Tatangelo
Istituto Nazionale Tumori "Fondazione Pascale"-IRCCS, 80131 Napoli, Italy.
Alessandra
A
Leone
CEINGE-Biotecnologie Avanzate, 80145 Napoli, Italy.
Giulia
G
Scalia
Istituto Nazionale Tumori "Fondazione Pascale"-IRCCS, 80131 Napoli, Italy.
Alfredo
A
Budillon
Laboratory of Drug Delivery, Department of Pharmacy, University of Napoli Federico II, 80131 Napoli, Italy.
Fabiana
F
Quaglia
Laboratory of Biochemistry, Department of Pharmacy, University of Napoli Federico II, 80131 Napoli, Italy.
Giulia
G
Russo
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002465:Cell Movement / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D003692:Delayed-Action Preparations; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers; D004339:Drug Compounding; D005260:Female; D005472:Fluorouracil / Q000737:chemistry / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D045325:HCT116 Cells; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D053758:Nanoparticles; D011108:Polymers / Q000737:chemistry*; D000090822:Ribosomal Protein L3; D012269:Ribosomal Proteins / Q000096:biosynthesis / Q000235:genetics*; D013997:Time Factors; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency* / Q000235:genetics
D000964:Antimetabolites, Antineoplastic; C497483:CD44 protein, human; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D018960:Hyaluronan Receptors; D011108:Polymers; C000716547:RPL3 protein, human; D000090822:Ribosomal Protein L3; D012269:Ribosomal Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D005472:Fluorouracil
5-FU; apoptosis; colon cancer; p53; ribosomal protein rpL3