G2 checkpoint abrogator abates the antagonistic interaction between antimicrotubule drugs and radiation therapy.
OBJECTIVE
We previously demonstrated that radiation may arrest tumor cells at G2 phase, which in turn prevents the cytotoxicity of antimicrotubule drugs and results in antagonistic interaction between these two modalities. Herein we tested whether G2 abrogators would attenuate the above antagonistic interaction and improve the therapeutic efficacy of combination therapy between radiation and antimicrotubule drugs.


METHODS
Breast cancer BCap37 and epidermoid carcinoma KB cell lines were administered with radiation, UCN-01 (a model drug of G2 abrogator), paclitaxel or vincristine, alone or in combinations. The antitumor activities of single and combined treatments were analyzed by a series of cytotoxic, apoptotic, cell cycle, morphological and biochemical assays.


RESULTS
UCN-01 significantly enhanced the cytotoxicity of radiation, antimitotic drugs, and their combined treatments in vitro. Further investigations demonstrated that UCN-01 attenuated radiation-induced G2 arrest, and subsequently repressed the inhibitory effect of radiation on drug-induced mitotic arrest and apoptosis.


CONCLUSIONS
This is the first report demonstrating that G2 checkpoint abrogation represses the inhibitory effect of radiation on antimicrotubule drugs, which may be implicated in cancer combination therapy. Considering that G2 abrogators are under extensive evaluation for cancer treatment, our findings provide valuable information for this class of promising compounds.
Program of Innovative Cancer Therapeutics, First Affiliated Hospital of Zhejiang University College of Medicine, Hangzhou, China.
Meihua
M
Sui
Hongfang
H
Zhang
Xiaoyun
X
Di
Jinjia
J
Chang
Youqing
Y
Shen
Weimin
W
Fan
D000704:Analysis of Variance; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000473:pathology / Q000628:therapy*; D016923:Cell Death / Q000187:drug effects / Q000528:radiation effects; D002455:Cell Division / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D059248:Chemoradiotherapy; D053938:DNA Fragmentation / Q000187:drug effects / Q000528:radiation effects; D005260:Female; D005434:Flow Cytometry; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects* / Q000528:radiation effects*; D006801:Humans; D008870:Microtubules / Q000187:drug effects; D017239:Paclitaxel / Q000494:pharmacology; D000091402:Prohibitins; D011839:Radiation, Ionizing; D019311:Staurosporine / Q000031:analogs & derivatives* / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000528:radiation effects; D014750:Vincristine / Q000494:pharmacology
D000970:Antineoplastic Agents; C000717331:PHB2 protein, human; D000091402:Prohibitins; D014750:Vincristine; C054852:7-hydroxystaurosporine; D019311:Staurosporine; D017239:Paclitaxel