Remarkable enhancement of cytotoxicity of onconase and cepharanthine when used in combination on various tumor cell lines

Abstract

Onconase (Onc), a ribonuclease from oocytes or early embryos of Northern Leopard frog (Rana pipiens), is cytostatic and cytotoxic to a variety of tumor lines in vitro, inhibits growth of tumors in animal in vivo models and is currently in Phase IIIb clinical trials for malignant mesothelioma where it displays antitumor activity with minor overall toxicity to the patient. One of the characteristic features of Onc is a synergism with a variety of other antitumor modalities. Cepharanthine (Cep), a biscoclaurine alkaloid from Stephania cepharantha Hayata, is widely used in Japan to treat variety of ailments. It also shows low toxicity to patients. The aim of the present study was to assess the interaction of these two drugs on different tumor cell lines. When human promyelocytic leukemia HL-60, histiomonocytic lymphoma U937, multiple myeloma RPMI-8228, prostate carcinoma DU 145 and prostate adenocarcinoma LNCaP cells were exposed to relatively low concentrations of Onc or Cep their growth rates were somewhat suppressed but the cells were still able to proliferate. Cell growth, however, was totally abolished in each of these cell lines when treated with Onc and Cep combined. The frequency of apoptosis was also many-fold higher in cultures treated with a combination of Onc and Cep than in respective cultures treated with Onc or Cep alone. The mechanism of the observed synergism is unclear but it may be associated with the Onc activity in targeting microRNAs and/or NFkappaB and Cep activity also targeting NFkappaB. The data suggest that the combination of these two drugs, that individually express a low toxic profile, may have strong antitumor potential.

RC-6 ribonuclease induces caspase activation, cellular senescence and neuron-like morphology in NT2 embryonal carcinoma cells

“…In the present study, we further demonstrated that RC-6 also exerted anticancer effects on human embryonal carcinoma cells (NT2 cells). The results suggested that RC-6 may exert anticancer effects on various types of cancer, such as the RC-RNase-and onconase-exerted anticancer effects (21,(26)(27)(28)(29)(30)(31). Although the mechanisms of RC-6-induced cell cytotoxicity on cervical cancer cells has not been studied (29), RC-6-induced cell cytotoxicity in HepG2 cells was related to caspase-9/-3 cascade (45).…”

“…Similar to RC-RNase, RC-6 (Rana catesbeiana ribonuclease-6) is also a frog ribonuclease derived from Rana catesbeiana (29,45). Previous studies demonstrated that onconase and RC-RNase can induce cell death in various cancer cells (21,(26)(27)(28)(29)(30)(31). However, only few studies showed that RC-6 inhibited cell growth in cervical cancer and hepatoma cells (29,45).…”

“…Both belong to the RNase A superfamily (22)(23)(24)(25). RC-RNase and onconase exert cytotoxic effects on various cancer cells such as hepatoma, cervical cancer, breast cancer, leukemia, mesothelioma, lung cancer, lymphoma, myeloma and prostate carcinoma (21,(26)(27)(28)(29)(30)(31). Although the mechanisms of frog ribonuclease-exerted cytotoxicity remain to be elucidated, it is noteworthy that RC-6 ribonuclease induces caspase activation, cellular senescence and neuron-like morphology in NT2 embryonal carcinoma cells GIOU-TENG YIANG 1,2* , HSIU-FENG TSAI 1* , JER-RONG CHEN 3* , PEI-LUN CHOU 4,5 , TSAI-KUN WU 6,7 , HSIAO-CHUN LIU 8 , WEI-JUNG CHANG 9 , onconase has been used as an anticancer drug in clinical trails (32)(33)(34)(35).…”

Rana catesbeiana ribonuclease induces cell apoptosis via the caspase-9/-3 signaling pathway in human glioblastoma DBTRG, GBM8901 and GBM8401 cell lines

“…In addition, numerous studies have indicated that RC-RNase is able to trigger distinct cell death mechanisms in various tumor cell types (10,11,14,17). By contrast, previous studies have also revealed that Onconase can exert antitumor activities in numerous tumor cells, including cervical, breast, colon, pancreatic and prostate cancer cells (12,(18)(19)(20)(21)(22).…”

Prospects of targeted therapy of acute leukemias in children

“…Фермент также потенцирует действие фактора не-кроза опухолей и апоптоз опухолевых клеток. Среди опухолей кроветворной системы к ранпирназе ока-зались чувствительными клетки промиелоцитарного лейкоза RPMI-8228 [14]. Применение фермента не сопровождается гематологической, кардио-и гепа-тотоксичностью.…”