Elimination of quiescent slow-cycling cells via reducing quiescence depth by natural compounds purified from Ganoderma lucidum

Abstract

The medical mushroom Ganoderma lucidum has long been used in traditional Chinese medicine and shown effective in the treatment of many diseases including cancer. Here we studied the cytotoxic effects of two natural compounds purified from Ganoderma lucidum, ergosterol peroxide and ganodermanondiol. We found that these two compounds exhibited cytotoxicity not only against fast proliferating cells, but on quiescent, slow-cycling cells. Using a fibroblast cell-quiescence model, we found that the cytotoxicity on quiescent cells was due to induced apoptosis, and was associated with a shallower quiescent state in compound-treated cells, resultant from the increased basal activity of an Rb-E2F bistable switch that controls quiescence exit. Accordingly, we showed that quiescent breast cancer cells (MCF7), compared to its non-transformed counterpart (MCF10A), were preferentially killed by ergosterol peroxide and ganodermanondiol treatment presumably due to their already less stable quiescent state. The cytotoxic effect of natural Ganoderma lucidum compounds against quiescent cells, preferentially on quiescent cancer cells vs. non-cancer cells, may help future antitumor development against the slow-cycling cancer cell subpopulations including cancer stem and progenitor cells.

Ergosterol peroxide inhibits ovarian cancer cell growth through multiple pathways

“…For example, G. lucidum extractions were reported to have hepatoprotective effects and induce apoptosis of HepG2 cells 23. EP is a natural product present in G. lucidum , which has been shown to regulate various biological processes including oxidation,12 inflammation,24 and tumor cell growth 25…”

Research progress on therapeutic targeting of quiescent cancer cells

“…Natural compounds purified from Ganoderma lucidum, ganodermanondiol, and ergosterol peroxide, play inhibitory roles via reducing the quiescence depth of cancer cells. Previous research has confirmed that these two compounds not only effectively inhibit rapidly proliferating cells but also activate the Rb-E2F bistable switch in quiescent slow-cycling cells, thereby reducing the quiescence depth of dormant cancer cells and enhancing their sensitivity to chemotherapeutic drugs [7]. Further studies on the effects of natural Ganoderma lucidum compounds on target quiescent cancer cells may present a new avenue for the development of novel chemotherapeutic agents.…”

“…Scientific literature to date supports the existence of quiescent cancer cells in many tumor types, including breast, liver and pancreatic cancer, acute myeloid leukaemia, melanoma, and glioblastoma [3,4]. In earlier studies, cells were induced to quiescence via serum starvation (whereby cells at low density were grown in serum-free medium) or contact inhibition (cells were grown in 10% serum until complete confluence) [5][6][7]. Quiescent cells were confirmed based on the lack of expression of Ki67 (a cell proliferation marker), negative EDU incorporation [7] or low rate of BrdU incorporation [3], and low Erk 1/2: p38 MAPK ratio [6][7][8].…”

“…In earlier studies, cells were induced to quiescence via serum starvation (whereby cells at low density were grown in serum-free medium) or contact inhibition (cells were grown in 10% serum until complete confluence) [5][6][7]. Quiescent cells were confirmed based on the lack of expression of Ki67 (a cell proliferation marker), negative EDU incorporation [7] or low rate of BrdU incorporation [3], and low Erk 1/2: p38 MAPK ratio [6][7][8]. Moreover, mVenus-p27K À , a fusion protein composed of the fluorescent protein mVenus and a defective mutant of p27 combined with Fucci probe could effectively recognize and distinguish cells at G0 from those at G1 during the G0-G1 transition state [9,10].…”

“…Reducing quiescence depth may awaken dormant CSCs, thus increasing their susceptibility to existing anticancer agents [7,52]. The Rb-E2F bistable switch plays critical roles in quiescence control.…”