New derivatives of the antimalarial drug Pyrimethamine in the control of melanoma tumor growth: an in vitro and in vivo study.
The antimalarial drug Pyrimethamine has been suggested to exert an antitumor activity by inducing apoptotic cell death in cancer cells, including metastatic melanoma cells. However, the dose of Pyrimethamine to be considered as an anticancer agent appears to be significantly higher than the maximum dose used as an antiprotozoal drug.



Hence, a series of Pyrimethamine analogs has been synthesized and screened for their apoptosis induction in two cultured metastatic melanoma cell lines. One of these analogs, the Methylbenzoprim, was further analyzed to evaluate cell-cycle and the mechanisms of cell death. The effects of Methylbenzoprim were also analyzed in a severe combined immunodeficiency (SCID)-mouse xenotransplantation model.



Low dose of Methylbenzoprim was capable of inducing cytotoxic activity and a potent growth-inhibitory effect by arresting cell cycle in S-phase in melanoma cells. Methylbenzoprim was also detected as powerful antineoplastic agents in SCID-mouse although used at very low dose and as a single agent.



Our screening approach led to the identification of a "low cost" newly synthesized drug (methylbenzoprim), which is able to act as an antineoplastic agent in vitro and in vivo, inhibiting melanoma tumor growth at very low concentrations.
Department of Therapeutic Research and Medicine Evaluation, Section of Cell Aging and Degeneration, Istituto Superiore di Sanita, 00161, Rome, Italy.
Chiara
C
Tommasino
Department of Therapeutic Research and Medicine Evaluation, Section of Cell Aging and Degeneration, Istituto Superiore di Sanita, 00161, Rome, Italy.
Lucrezia
L
Gambardella
Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
Maria
M
Buoncervello
Newcastle Cancer Centre, Northern Institute for Cancer Research, School of Chemistry, Bedson Building, Newcastle University, Newcastle upon Tyne, NE1 7RU, UK.
Roger J
RJ
Griffin
Newcastle Cancer Centre, Northern Institute for Cancer Research, School of Chemistry, Bedson Building, Newcastle University, Newcastle upon Tyne, NE1 7RU, UK.
Bernard T
BT
Golding
Department of Therapeutic Research and Medicine Evaluation, Section of Cell Aging and Degeneration, Istituto Superiore di Sanita, 00161, Rome, Italy.
Manuela
M
Alberton
Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
Daniele
D
Macchia
Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
Massimo
M
Spada
Department of Radiological, Oncological and Pathological Sciences, Sapienza University of Rome, Policlinico Umberto I, Rome, Italy.
Bruna
B
Cerbelli
Department of Radiological, Oncological and Pathological Sciences, Sapienza University of Rome, Policlinico Umberto I, Rome, Italy.
Giulia
G
d'Amati
Department of Therapeutic Research and Medicine Evaluation, Section of Cell Aging and Degeneration, Istituto Superiore di Sanita, 00161, Rome, Italy. malorni@iss.it.
Walter
W
Malorni
Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
Lucia
L
Gabriele
Department of Therapeutic Research and Medicine Evaluation, Section of Cell Aging and Degeneration, Istituto Superiore di Sanita, 00161, Rome, Italy.
Anna Maria
AM
Giammarioli
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000494:pharmacology; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D009362:Neoplasm Metastasis; D011739:Pyrimethamine / Q000031:analogs & derivatives*; D011743:Pyrimidines / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D011743:Pyrimidines; C064625:methylbenzoprim; D020169:Caspases; D011739:Pyrimethamine
Antifolates; Antimalarial Drugs; Apoptosis; Chemotherapy; Drug repurposing; Melanoma