No evident dose-response relationship between cellular ROS level and its cytotoxicity--a paradoxical issue in ROS-based cancer therapy.
Targeting cancer via ROS-based mechanism has been proposed as a radical therapeutic approach. Cancer cells exhibit higher endogenous oxidative stress than normal cells and pharmacological ROS insults via either enhancing ROS production or inhibiting ROS-scavenging activity can selectively kill cancer cells. In this study, we randomly chose 4 cancer cell lines and primary colon or rectal cancer cells from 4 patients to test the hypothesis and obtained following paradoxical results: while piperlongumin (PL) and β-phenylethyl isothiocyanate (PEITC), 2 well-defined ROS-based anticancer agents, induced an increase of cellular ROS and killed effectively the tested cells, lactic acidosis (LA), a common tumor environmental factor that plays multifaceted roles in promoting cancer progression, induced a much higher ROS level in the tested cancer cells than PL and PEITC, but spared them; L-buthionine sulfoximine (L-BSO, 20 μM) depleted cellular GSH more effectively and increased higher ROS level than PL or PEITC but permitted progressive growth of the tested cancer cells. No evident dose-response relationship between cellular ROS level and cytotoxicity was observed. If ROS is the effecter, it should obey the fundamental therapeutic principle - the dose-response relationship. This is a major concern.
Cancer Institute (Key Laboratory for Cancer Intervention and Prevention, China National Ministry of Education, Zhejiang Provincial Key Laboratory of Molecular Biology in Medical Sciences), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Chunpeng
C
Zhu
School of Life Sciences and Biotechnologies, China Pharmaceutical University, Nanjing, China.
Wei
W
Hu
Cancer Institute (Key Laboratory for Cancer Intervention and Prevention, China National Ministry of Education, Zhejiang Provincial Key Laboratory of Molecular Biology in Medical Sciences), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Hao
H
Wu
Cancer Institute (Key Laboratory for Cancer Intervention and Prevention, China National Ministry of Education, Zhejiang Provincial Key Laboratory of Molecular Biology in Medical Sciences), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Xun
X
Hu
D000140:Acidosis, Lactic / Q000503:physiopathology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D004148:Dioxolanes / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D017879:Isothiocyanates / Q000494:pharmacology; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D018384:Oxidative Stress / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D010881:Piperidones
D000970:Antineoplastic Agents; D000975:Antioxidants; D004148:Dioxolanes; D005978:Glutathione; D017879:Isothiocyanates; D017382:Reactive Oxygen Species; C058305:phenethyl isothiocyanate; C498077:piperlongumine; D010881:Piperidones