Efficacy of the HSP70 inhibitor PET-16 in multiple myeloma

Abstract

Multiple myeloma (MM) is a common and largely incurable blood cancer for which new treatment options are needed, as resistance to current modalities is an issue. Additionally, because this tumor type often resides in a hypoxic niche of the bone marrow, new therapeutics that remain effective even under hypoxic conditions are sought. Because of the secretory nature of MM cells they are uniquely under proteotoxic stress, and we hypothesized that these tumor cells may alleviate this stress by upregulating the major stress-induced cytosolic form of the chaperone HSP70. In this work we test the efficacy of the HSP70 inhibitor PET-16 for MM. We show that MM cell lines express significant levels of HSP70, and further that inhibition of HSP70 causes decreased viability and apoptosis, along with proteotoxic stress, as assessed by the accumulation of poly-ubiquitylated proteins. Importantly, we show that growth of these tumor cells under hypoxic conditions has no effect on the ability of PET-16 to be cytotoxic. The HSP70 inhibitor PET-16 should thus be considered further for pre-clinical analyses of efficacy in MM.

The isopeptidase inhibitor 2cPE triggers proteotoxic stress and ATM activation in chronic lymphocytic leukemia cells

“…Malignant cells exhibit higher levels of proteotoxic stress, as a consequence of their higher proliferative and mutational status [35–38]. This peculiarity renders cancer cells more dependent on the UPS and more vulnerable to its inhibitors or to inducers of proteotoxic stress [39, 40]. We propose that 2cPE and similar compounds are efficient anti-neoplastic drugs in vivo , because they elicit a vicious cycle, by triggering proteotoxic stress in cancer cells, which already exhibit high level of such stress.…”

The Biology of Aging and Cancer: A Brief Overview of Shared and Divergent Molecular Hallmarks

“…In preclinical trials the combination of a HSP90 inhibitor with radiotherapy shows great results in the usually radiochemotherapy resistant hepatocellular carcinoma[ 81 ]. HSP70 inhibitors have shown preclinical anti-cancer effects in multiple myeloma [ 82 ], and a HSP27 inhibitor has shown effect in castration resistant prostate cancer and is now undergoing phase 2 clinical trial [ 83 ]. Chaperone targeting drugs show promise as a new group within cancer therapy and a several avenues of research is currently ongoing.…”

Crystal Structure of Bis(2,4,6-trimethylphenyl)-phosphine Oxide

“…The importance of organophosphorus compounds is illustrated by their widespread applications in areas of organic [1,2], inorganic [3,4], medicinal [5][6][7][8], and material [9] chemistries. Over the past decade, the synthetic potential of secondary phosphine oxides has become increasingly well-established.…”