Cisplatin and ultra-violet-C synergistically down-regulate receptor tyrosine kinases in human colorectal cancer cells.
BACKGROUND
Platinum-containing anti-cancer drugs such as cisplatin are widely used for patients with various types of cancers, however, resistance to cisplatin is observed in some cases. Whereas we have recently reported that high dose UV-C (200 J/m²) induces colorectal cancer cell proliferation by desensitization of EGFR, which leads oncogenic signaling in these cells, in this study we investigated the combination effect of low dose cisplatin (10 μM) and low dose UV-C (10 J/m²) on cell growth and apoptosis in several human colorectal cancer cells, SW480, DLD-1, HT29 and HCT116.


RESULTS
The combination inhibited cell cycle and colony formation, while either cisplatin or UV-C alone had little effect. The combination also induced apoptosis in these cells. In addition, the combination caused the downregulation of EGFR and HER2. Moreover, UV-C alone caused the transient internalization of the EGFR, but with time EGFR recycled back to the cell surface, while cisplatin did not affect its localization. Surprisingly, the combination caused persistent internalization of the EGFR, which results in the lasting downregulation of the EGFR.


CONCLUSIONS
The combination of low dose cisplatin and low dose UV-C synergistically exerted anti-cancer effect by down-regulating RTK, such as EGFR and HER2. These findings may provide a novel strategy for the treatment of patients with colorectal cancer.
Departments of Gastroenterology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan.
Junji
J
Kawaguchi
Seiji
S
Adachi
Ichiro
I
Yasuda
Takahiro
T
Yamauchi
Masanori
M
Nakashima
Tomohiko
T
Ohno
Masahito
M
Shimizu
Takashi
T
Yoshioka
Masahiko
M
Itani
Osamu
O
Kozawa
Hisataka
H
Moriwaki
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D002945:Cisplatin / Q000494:pharmacology*; D015179:Colorectal Neoplasms / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects* / Q000528:radiation effects*; D066246:ErbB Receptors / Q000378:metabolism; D006801:Humans; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D014410:Tumor Stem Cell Assay; D014466:Ultraviolet Rays
D000970:Antineoplastic Agents; D002945:Cisplatin; D066246:ErbB Receptors; D011838:Radiation-Sensitizing Agents; D020794:Receptor Protein-Tyrosine Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases