Abstract
We identified pyrvinium pamoate, an old anthelminthic medicine, which preferentially inhibits anchorage-independent growth of cancer cells over anchorage-dependent growth (∼10 fold). It was also reported by others to have anti-tumor activity in vivo and selective toxicity against cancer cells under glucose starvation in vitro, but with unknown mechanism. Here, we provide evidence that pyrvinium suppresses the transcriptional activation of GRP78 and GRP94 induced by glucose deprivation or 2-deoxyglucose (2DG, a glycolysis inhibitor), but not by tunicamycin or A23187. Other UPR pathways induced by glucose starvation, e.g. XBP-1, ATF4, were also found suppressed by pyrvinium. Constitutive expression of GRP78 via transgene partially protected cells from pyrvinium induced cell death under glucose starvation, suggesting that suppression of the UPR is involved in pyrvinium mediated cytotoxicity under glucose starvation. Xenograft experiments showed rather marginal overall anti-tumor activity for pyrvinium as a monotherapy. However, the combination of pyrvinium and Doxorubicin demonstrated significantly enhanced efficacy in vivo, supporting a mechanistic treatment concept based on tumor hypoglycemia and UPR.
Highlights
Intratumoral heterogeneity is a common characteristic of solid tumors [1]
Anchorage-independent growth of cancer cells is a hallmark of cell transformation
Pyrvinium pamoate was identified among the hits with preferential inhibitory activity for anchorage-independent growth (Figure 1B) over anchorage-dependent growth (Figure 1A) measured by liquid culture (LIQ) growth
Summary
Intratumoral heterogeneity is a common characteristic of solid tumors [1]. As tumors progress and increase in size, cancer cells located in certain parts of the tumor interior, are confronted with hypoglycemia and hypoxia resulting from poor vascularization. The hypoglycemic state of cancer cells within solid tumors are usually further enhanced by the high energy demand met mainly through enhanced glycolysis, or the Warburg effect. Cancer cells under these stressful microenvironments become dormant and resistant to radiation and chemotherapy, while actively dividing cancer cells located at areas with sufficient blood supply, such as outer layers of tumors, are killed by these treatments [2,3,4]. Studies in the recent decade have presented a complex network of signaling pathways activated by the UPR following ER stress, involving key proteins e.g. GRP78, GRP94, ATF-6, ATF-4, PERK, IREa, XBP-1 (Figure S1)
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