Background: Dihydroartemisinin 40mg and piperaquine phosphate 320mg (DHA-PQP) drug combination and piperaquin phosphate (PQP) material was first successfully produced in Vietnam \r\n', u'Objective: to study influences of the fixed combination antimalaria drug dihydroartemisinin plus piperaquine in reproductive progress of mice\r\n', u"Subjects and methods: This study was carried out at the Department of Malaria treatment and research, National Institute of Malariology, Parasitology and Entomology (NIMPE), between September, 2006 and March, 2007. The influences of the fixed combination antimalarial drug 40 mg dihydroartemisinin (DHA) plus 320 mg piperaquine phosphate (PQP), with PQP produced firstly in Vietnam, in mice's reproductive progresses were investigated in three generations (including the parent and FI, F2 child generations). \r\n", u'Results: In all three generations, study indices among the treated and control groups were not significantly different (the values P > 0.05). These indices included the rate of fecundation, numbers of fetuses of each mother mouse, numbers of offspring of each mother mouse, mean body weights of offspring. Early lethal fetuses, lately lethal fetuses, monsters and innate abnormally offspring were not found in P, FI and F2 generations. The necessary feeding - day numbers that offspring of P and F 1 generations reached their body weights about 20g were different insignificantly (the values P> 0.05) among the treated and control groups. \r\n', u'Conclusion: The combination DHA-PQP was found to cause no genome mutations in mice at the oral dose of 120 mg per kg per day for 5 consecutive days. \r\n', u'
Dihydroartemisinin ; piperaquine ; fixed combination antimalarial drug ; rate of fecundation ; early lethal fetuses ; lately lethal fetuses ; monsters and innate abnormally offspring ; genome mutations ; fetuses

Metformin is currently a strong candidate anti-tumor agent in multiple cancers. However, its anti-tumor effectiveness varies among different cancers or subpopulations, potentially due to tumor heterogeneity. It thus remains unclear which hepatocellular carcinoma (HCC) patient subpopulation(s) can benefit from metformin treatment. Here, through a genome-wide CRISPR-Cas9-based knockout screen, we find that DOCK1 levels determine the anti-tumor effects of metformin and that DOCK1 is a synthetic lethal target of metformin in HCC. Mechanistically, metformin promotes DOCK1 phosphorylation, which activates RAC1 to facilitate cell survival, leading to metformin resistance. The DOCK1-selective inhibitor, TBOPP, potentiates anti-tumor activity by metformin in vitro in liver cancer cell lines and patient-derived HCC organoids, and in vivo in xenografted liver cancer cells and immunocompetent mouse liver cancer models. Notably, metformin improves overall survival of HCC patients with low DOCK1 levels but not among patients with high DOCK1 expression. This study shows that metformin effectiveness depends on DOCK1 levels and that combining metformin with DOCK1 inhibition may provide a promising personalized therapeutic strategy for metformin-resistant HCC patients.
Animals ; Antineoplastic Agents/therapeutic use* ; Carcinoma, Hepatocellular/metabolism* ; Cell Line, Tumor ; Clustered Regularly Interspaced Short Palindromic Repeats ; Genome ; Humans ; Liver Neoplasms/metabolism* ; Metformin/therapeutic use* ; Mice ; Phosphorylation ; Synthetic Lethal Mutations ; Transcription Factors/metabolism* ; rac GTP-Binding Proteins/metabolism*