Anti-adult T-cell leukemia/lymphoma effects of indole-3-carbinol.
BACKGROUND
Adult T-cell leukemia/lymphoma (ATLL) is a malignancy derived from T cells infected with human T-cell leukemia virus type 1 (HTLV-1), and it is known to be resistant to standard anticancer therapies. Indole-3-carbinol (I3C), a naturally occurring component of Brassica vegetables such as cabbage, broccoli and Brussels sprout, is a promising chemopreventive agent as it is reported to possess antimutagenic, antitumorigenic and antiestrogenic properties in experimental studies. The aim of this study was to determine the potential anti-ATLL effects of I3C both in vitro and in vivo.


RESULTS
In the in vitro study, I3C inhibited cell viability of HTLV-1-infected T-cell lines and ATLL cells in a dose-dependent manner. Importantly, I3C did not exert any inhibitory effect on uninfected T-cell lines and normal peripheral blood mononuclear cells. I3C prevented the G1/S transition by reducing the expression of cyclin D1, cyclin D2, Cdk4 and Cdk6, and induced apoptosis by reducing the expression of XIAP, survivin and Bcl-2, and by upregulating the expression of Bak. The induced apoptosis was associated with activation of caspase-3, -8 and -9, and poly(ADP-ribose) polymerase cleavage. I3C also suppressed IkappaBalpha phosphorylation and JunD expression, resulting in inactivation of NF-kappaB and AP-1. Inoculation of HTLV-1-infected T cells in mice with severe combined immunodeficiency resulted in tumor growth. The latter was inhibited by treatment with I3C (50 mg/kg/day orally), but not the vehicle control.


CONCLUSIONS
Our preclinical data suggest that I3C could be potentially a useful chemotherapeutic agent for patients with ATLL.
Machijima
Yoshiaki
Y
Division of Molecular Virology and Oncology, Graduate School of Medicine, University of the Ryukyus, Nishihara, Okinawa, Japan. k078771@eve.u-ryukyu.ac.jp
Ishikawa
Chie
C
Sawada
Shigeki
S
Okudaira
Taeko
T
Uchihara
Jun-nosuke
JN
Tanaka
Yuetsu
Y
Taira
Naoya
N
Mori
Naoki
N
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000187:drug effects; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects*; D016193:G1 Phase / Q000187:drug effects; D015368:Human T-lymphotropic virus 1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D013601:T-Lymphocytes / Q000187:drug effects / Q000821:virology; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D007211:Indoles; C016517:indole-3-carbinol