Culture at a Higher Temperature Mildly Inhibits Cancer Cell Growth but Enhances Chemotherapeutic Effects by Inhibiting Cell-Cell Collaboration.
Acute febrile infections have historically been used to treat cancer. To explore the underlying mechanism, we studied chronic effects of fever on cancer cell growth and chemotherapeutic efficacy in cell culture. We found that culturing cancer cells at 39°C mildly inhibited cell growth by arresting the cells at the G1 phase of the cell cycle. When cells were seeded in culture dishes at a lower density, e.g. about 1000-2000 cells per 35-mm dish, the growth inhibition was much greater, manifested as many fewer cell colonies in the 39°C dishes, compared with the results at a higher density seeding, e.g. 20,000 cells per dish, suggesting that cell-cell collaboration as the Allee effect in cell culture is inhibited at 39°C. Withdrawal of cells from serum enhanced the G1 arrest at 39°C and, for some cell lines such as A549 lung cancer cells, serum replenishment failed to quickly drive the cells from the G1 into the S and G2-M phases. Therapeutic effects of several chemotherapeutic agents, including clove bud extracts, on several cancer cell lines were more potent at 39°C than at 37°C, especially when the cells were seeded at a low density. For some cell lines and some agents, this enhancement is long-lasting, i.e. continuing after the cessation of the treatment. Collectively these results suggest that hyperthermia may inhibit cancer cell growth by G1 arrest and by inhibition of cell-cell collaboration, and may enhance the efficacy of several chemotherapeutic agents, an effect which may persist beyond the termination of chemotherapy.
Hormel Institute, University of Minnesota, Austin, Minnesota, 55912, United States of America; Department of Oncology, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei Province, 442000, P.R. China.
Shengming
S
Zhu
Hormel Institute, University of Minnesota, Austin, Minnesota, 55912, United States of America.
Jiangang
J
Wang
Hormel Institute, University of Minnesota, Austin, Minnesota, 55912, United States of America.
Bingkun
B
Xie
Department of Oncology, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei Province, 442000, P.R. China.
Zhiguo
Z
Luo
Department of Pharmacology, Capital Medical University, 10 West, Youanmen Outside, Beijing, 100069, China.
Xiukun
X
Lin
Hormel Institute, University of Minnesota, Austin, Minnesota, 55912, United States of America.
D Joshua
DJ
Liao
D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D002450:Cell Communication / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D048430:Cell Shape / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002945:Cisplatin / Q000494:pharmacology; D045783:Clove Oil / Q000494:pharmacology; D004357:Drug Synergism; D005472:Fluorouracil / Q000494:pharmacology; D016193:G1 Phase / Q000187:drug effects; D006358:Hot Temperature; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D044967:Serum
D000970:Antineoplastic Agents; D045783:Clove Oil; D002945:Cisplatin; D005472:Fluorouracil