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

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.

Temperature induces significant changes in both glycolytic reserve and mitochondrial spare respiratory capacity in colorectal cancer cell lines

“…The cancer literature reports use of different protocols involving exposure of cell lines to hyperthermia from 1 hour 13 up to 3 days 3 , and some cases up for 2 weeks 14 (in most cases 12–36 h) which makes difficult to draw direct parallels between possible molecular mechanisms underlying the in vitro results and the outcomes of the human hyperthermia clinical studies. The Seahorse extracellular flux analyzer has been reported to produce valuable data measuring cancer metabolism under different experimental conditions including, but not limited to the following: testing effects on novel therapies 15–17 , changes in cancer cell substrate preferences 18–20 , effects of gene overexpression or knockdown in cancer cells 21–23 , effects of hypoxia 20, 24 and cell environmental factors 25–27 .…”

“…Most experimental evidence underlying this theory is from in vitro studies in which cell cultures were exposed to prolonged periods (24–72 h) of hyperthermia (defined as exposure to 39° – 42°C). In a recent study, Zhu et al, (2015) reported that various cancer cells maintained at 39°C for 72 h demonstrated mild inhibition of cell growth by arresting the cells at the G1 phase of the cell cycle which also resulted in hyperthermia-enhanced efficacy of several chemotherapeutic agents 3 . In contrast to the in vitro experiments, the clinical in vivo protocols typically utilize only short-term exposure to hyperthermia.…”

Learning about the Importance of Mutation Prevention from Curable Cancers and Benign Tumors

“…First, cancer cells recruit normal stromal cells to establish cancer niches, as exemplified by tumor angiogenesis 23 . Second, cancer cells collaborate with each other 1 ; 2 ; 34 , which is evident not only in vivo, as in their collective invasion in patients 35 and clonal cooperation in animals 36 ; 37 , but also in vitro as demonstrated by the fact that many cancer cell lines cannot survive in a culture dish when cells are seeded in a very low density 34 ; 38 . On the other hand, there are also many fights among different cell types.…”

A mechanistic kinetic description of lactate dehydrogenase elucidating cancer diagnosis and inhibitor evaluation

“…These molecules are able to seize the available substrate-binding sites and further inhibit substrate binding and reactivity. Meanwhile, tumor cells respond differently from normal cells to temperature changes 8 . Therefore, a universal method to quantitatively describe the kinetic properties of LDH and evaluate the effect of inhibitors and temperature can be beneficial for cancer study.…”