Abstract
Chemotherapy in patients with inoperable or advanced breast cancer inevitably results in low-dose exposure of tumor-cell subset and senescence. Metabolically active senescent cells secrete multiple tumor promoting factors making their elimination a therapeutic priority. Viscum album is one of the most widely used alternative anti-cancer medicines facilitating chemotherapy tolerance of breast cancer patients. The aim of this study was to model and investigate how Viscum album extracts execute additive anti-tumor activity with low-dose Dox using ER + MCF7 breast cancer cells. We report that cotreatment of MCF7 with Viscum album and Dox abrogates G2/M cycle arrest replacing senescence with intrinsic apoptotic program. Mechanistically, this switch was associated with down-regulation of p21, p53/p73 as well as Erk1/2 and p38 activation. Our findings, therefore, identify a novel mechanistic axis of additive antitumor activity of Viscum album and low dose-Dox. In conclusion, ER + breast cancer patients may benefit from addition of Viscum album to low-dose Dox chemotherapy due to suppression of cancer cell senescence and induction of apoptosis.
Highlights
Chemotherapy in patients with inoperable or advanced breast cancer inevitably results in low-dose exposure of tumor-cell subset and senescence
We have previously shown that Viscum album/aqueous extract (VAE) increases anti-leukemic effectiveness of doxorubicin by preventing G2/M arrest and inducing apoptosis[66]
Baring in mind that low-dose chemotherapy induces cell cycle arrest and senescence, we wanted to ask the question whether Mistletoe extract (Isc Qu) anti-tumor activity targets this cell population
Summary
Chemotherapy in patients with inoperable or advanced breast cancer inevitably results in low-dose exposure of tumor-cell subset and senescence. Though TIS has been long considered a desirable therapeutic outcome and a promising strategy in overcoming therapy resistance[13,14,15], a growing body of work has indicated that TIS cells may alter response to chemotherapy[16], escape cell cycle arrest[17, 18] and promote tumor growth[19] (reviewed in refs[20,21]) Most of these detrimental effects have been attributed to both autocrine and paracrine activity of senescent cell secretome designated as Senescence Associated Secretory Phenotype or SASP. Under conditions of persistent tissue injury, damaged normal and tumor cells undergo immunoediting escaping immune surveillance[35], an effect recently linked to SASP secretome[36]
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