Culture at a Higher Temperature Mildly Inhibits Cancer Cell Growth but Enhances Chemotherapeutic Effects by Inhibiting Cell-Cell Collaboration.

Jiangang Wang,Bingkun Xie,Shengming Zhu,Arun Rishi,Zhiguo Luo,D Joshua Liao,Xiukun Lin

doi:10.1371/journal.pone.0137042

Abstract

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.

Highlights

Acute febrile infections by different pathogens have for centuries been thought to play a role in cancer prophylaxis [1,2] and in cancer spontaneous regression [3,4,5,6,7], as reviewed before by us [8] and others [9]
About 500 of the 1000 patients so treated by Coley and others showed tumor regression [15,16,17,18]. This bacterial mixture, dubbed as “Coley’s vaccine” or “Coley’s toxin”, is an immunotherapy [15] and works through hyperthermia (HT), because its efficacy largely depended on whether the patients responded with higher fevers [10,16]
Hela cervical cancer cell line, A549 and H1650 non-small cell lung cancer cell lines, HCT116 colorectal cancer cell line, as well as HEK293T (T large antigen expressing human embryonic kidney) cell line were originally purchased from American Type Cell Culture (ATCC) and used in the study

Summary

Introduction

Acute febrile infections by different pathogens have for centuries been thought to play a role in cancer prophylaxis [1,2] and in cancer spontaneous regression [3,4,5,6,7], as reviewed before by us [8] and others [9]. About 500 of the 1000 patients so treated by Coley and others showed tumor regression [15,16,17,18] This bacterial mixture, dubbed as “Coley’s vaccine” or “Coley’s toxin”, is an immunotherapy [15] and works through hyperthermia (HT), because its efficacy largely depended on whether the patients responded with higher fevers [10,16]. Many cancer patients manifest hypothermia or feel “cold” during chemotherapy, possibly because the body mistakes the chemo drug for a toxin and lowers the temperature to minimize its “toxicity” [22] If this conjecture is correct, raising the body temperature may restore the chemo efficacy

Methods

Results

Conclusion