Abstract
It is acknowledged that cancer cells are able to undergo senescence in response to clinically used chemotherapeutics. Moreover, recent years have provided evidence that some drugs can selectively remove senescent cells. Therefore, it is essential to properly identify and characterize senescent cells, especially when it comes to cancer. Senescence was induced in various cancer cell lines (A549, SH-SY-5Y, HCT116, MDA-MB-231, and MCF-7) following treatment with doxorubicin, irinotecan, methotrexate, 5-fluorouracil, oxaliplatin, or paclitaxel. Treatment with tested chemotherapeutics resulted in upregulation of p21 and proliferation arrest without cytotoxicity. A comparative analysis with the use of common senescence markers (i.e., morphology, SA-β-galactosidase, granularity, secretory phenotype, and the level of double-stranded DNA damage) revealed a large diversity in response to the chemotherapeutics used. The strongest senescence inducers were doxorubicin, irinotecan, and methotrexate; paclitaxel had an intermediate effect and oxaliplatin and 5-fluorouracil did not induce senescence. In addition, different susceptibility of cancer cells to senescence was observed. A statistical analysis aimed at finding any relationship between the senescence markers applied did not show clear correlations. Moreover, increased SA-β-gal activity coupled with p21 expression proved not to be an unequivocal senescence marker. This points to a need to simultaneously analyze multiple markers, given their individual limitations.
Highlights
The rationale behind anticancer strategies is to kill rapidly dividing cancer cells by high doses of drugs or irradiation
We used drug concentrations that yielded the highest number of SA-β-gal-positive cells without a cytotoxic effect
Our results revealed that the number of double-strand breaks (DSBs), visualized by γH2AX foci, was generally higher on day D1+3 than immediately after drug removal on day D1; there were drug and cell differences in the numbers of DNA damage foci
Summary
The rationale behind anticancer strategies is to kill rapidly dividing cancer cells by high doses of drugs or irradiation. Delayed side effects of anticancer treatment, such as recurrence and secondary cancers, are still serious problems for cancer survivors and clinicians and raise the question concerning the resistance of cancer cells to treatment. One reason for cancer recurrence could be the cytostatic instead of cytotoxic effect of anticancer treatment. It has already been 20 years since anticancer treatment was shown to induce cellular senescence [1] Subsequently, therapy-induced senescence (TIS) has been recognized as an effective way to treat cancer while lessening side effects [2,3]. A new paradigm of senescent cell therapy has been developed [5] and a new class of drugs—senolytics—has been
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