Exploring long-term protection of normal human fibroblasts and epithelial cells from chemotherapy in cell culture

Abstract

Killing of proliferating normal cells limits chemotherapy of cancer. Several strategies to selectively protect normal cells were previously suggested. Here we further explored the protection of normal cells from cell cycle-specific chemotherapeutic agents such as mitotic inhibitors (MI). We focused on a long-term cell recovery (rather than on a short-term cell survival) after a 3-day exposure to MI (paclitaxel and nocodazole). In three normal human cell types (RPE, NKE, WI-38t cells) but not in cancer cells with mutant p53, pre-treatment with nutlin-3a, a non-genotoxic inducer of wt p53, caused G1 and/or G2 arrest, thus preventing lethal mitotic arrest caused by MI and allowing normal cells to recover after removal of MI. Rapamycin, an inhibitor of the nutrient-sensing mTOR pathway, potentiated the protective effect of nutlin-3a in normal cells. Also, a combination of rapamycin and metformin, an anti-diabetic drug, induced G1 and G2 arrest selectively in normal cells and thereby protected them from MI. A combination of metformin and rapamycin also protected normal cells in low glucose conditions, whereas in contrast it was cytotoxic for cancer cells. Based on these data and the analysis of the literature, we suggest that a rational combination of metformin and rapamycin can potentiate chemotherapy with mitotic inhibitors against cancer, while protecting normal cells, thus further increasing the therapeutic window.

p53 expression controls prostate cancer sensitivity to chemotherapy and the MDM2 inhibitor Nutlin-3

“…To do this, we turned to the use of a MDM2-specific inhibitor, Nutlin-3. 3,7,[20][21][22][50][51][52] LNCaP cells express two wild-type TP53 alleles and demonstrated the most significant cellular response to alterations in p53 signaling when mutant DN p53DD was introduced. Therefore, we next performed MTT analysis with LNCaP cells treated with a constant concentration of Nutlin-3 performed.…”

“…2 p53 is a sequence-specific transcription factor, the protein product of the TP53 gene (chromosome band 17p13.1), whose expression is increased in response to cellular stresses that cause DNA damage, such as UV radiation, cytotoxic drugs or hypoxia. [3][4][5] Furthermore, chemotherapeutic drug dosage may regulate the induction of quiescence or senescence as well as affect aging. [6][7][8][9] In a homeostatic state, cells produce and degrade low but equal concentrations of p53 protein, causing rapid turnover of the factor, the half-life being approximately 20 min.…”

Overcoming resistance to mTOR inhibition for enhanced strategies in clinical trials

“…The drug combination accomplished these results by selectively inducing G1 and G2 arrest in normal cells. Metformin and rapamycin protected normal cells in low-glucose conditions, but the combination was cytotoxic to cancer cells [45].…”

“…The combination of rapamycin and metformin, an antidiabetic drug, was shown to expand the therapeutic window of normal human cell types (RPE, NKE, WI-38t cells) exposed to paclitaxel and nocodazole, both of which are microtubule inhibitors [45]. The drug combination accomplished these results by selectively inducing G1 and G2 arrest in normal cells.…”

The power of chemotherapeutic engineering: Arresting cell cycle and suppressing senescence to protect from mitotic inhibitors

“…p53-inducing drugs cannot protect cancer cells lacking wt p53. 36,[42][43][44][45][46][47][48][49][50][51][52][53] One concern is that "protective drugs" may cause senescence in normal cells. So the goal is to induce arrest and suppress cells ( Fig.…”