Derivatives of Procaspase-Activating Compound 1 (PAC-1) and their Anticancer Activities

Roth, Howard S.; Hergenrother, Paul J.

doi:10.2174/0929867323666151127201829

Cited by 34 publications

(36 citation statements)

References 104 publications

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“…PAC-1 competes with procaspase-3 for loosely-bound zinc, activating its cleavage to caspase-3 and leading to apoptosis. The weak affinity of PAC-1 for zinc limits the potential for off-target effects that would result from competition for tightly-bound zinc in proteins like the matrix metalloproteinases [17]. …”

Section: Metal-binding Chelators and Metal-releasing Ionophoresmentioning

confidence: 99%

Developing drugs targeting transition metal homeostasis

Weekley

2017

Current Opinion in Chemical Biology

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Metal dyshomeostasis is involved in the pathogenesis and progression of diseases including cancer and neurodegenerative diseases. Metal chelators and ionophores are well known modulators of transition metal homeostasis, and a number of these molecules are in clinical trials. Metalbinding compounds are not the only drugs capable of targeting transition metal homeostasis. This review presents recent highlights in the development of chelators and ionophores for the treatment of cancer and neurodegenerative disease. Moreover, we discuss the development of small molecules that alter copper and iron homeostasis by inhibiting metal transport proteins. Finally, we consider the emergence of metal regulatory factor 1 as a drug target in diseases where it mediates zinc-induced signalling cascades leading to pathogenesis.

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Section: Metal-binding Chelators and Metal-releasing Ionophoresmentioning

confidence: 99%

Developing drugs targeting transition metal homeostasis

Weekley

2017

Current Opinion in Chemical Biology

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“…A further challenge in treating glioblastoma is its intrinsic resistance to apoptosis, through the overexpression of anti-apoptotic proteins such as Bcl-2 [ 7 , 8 ], and other mechanisms. Analysis of primary tumor samples and cancer cell lines have shown procaspase-3 levels to be elevated in numerous cancer types [ 9 ]. Thus, although common hallmarks of cancers are malignant alterations that inhibit apoptotic signaling [ 10 ], these cells paradoxically express elevated levels of the executioner caspase responsible for carrying out the cellular proteolysis.…”

Section: Introductionmentioning

confidence: 99%

Synergistic and targeted therapy with a procaspase-3 activator and temozolomide extends survival in glioma rodent models and is feasible for the treatment of canine malignant glioma patients

et al. 2017

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PurposeGlioblastoma is a deadly brain cancer with a median survival time of ∼15 months. Ionizing radiation plus the DNA alkylator temozolomide (TMZ) is the current standard therapy. PAC-1, a procaspase-3 activating small molecule, is blood-brain barrier penetrant and has previously demonstrated ability to synergize with diverse pro-apoptotic chemotherapeutics. We studied if PAC-1 could enhance the activity of TMZ, and whether addition of PAC-1 to standard treatment would be feasible in spontaneous canine malignant gliomas.Experimental DesignUsing cell lines and online gene expression data, we identified procaspase-3 as a potential molecular target for most glioblastomas. We investigated PAC-1 as a single agent and in combination with TMZ against glioma cells in culture and in orthotopic rodent models of glioma. Three dogs with spontaneous gliomas were treated with an analogous human glioblastoma treatment protocol, with concurrent PAC-1.ResultsProcaspase-3 is expressed in gliomas, with higher gene expression correlating with increased tumor grade and decreased prognosis. PAC-1 is cytotoxic to glioma cells in culture and active in orthotopic rodent glioma models. PAC-1 added to TMZ treatments in cell culture increases apoptotic death, and the combination significantly increases survival in orthotopic glioma models. Addition of PAC-1 to TMZ and radiation was well-tolerated in 3 out of 3 pet dogs with spontaneous glioma, and partial to complete tumor reductions were observed.ConclusionsProcaspase-3 is a clinically relevant target for treatment of glioblastoma. Synergistic activity of PAC-1/TMZ in rodent models and the demonstration of feasibility of the combined regime in canine patients suggest potential for PAC-1 in the treatment of glioblastoma.

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“…25,29,30 Procaspase-activating compound 1 (PAC-1) (Figure 1a) is a small-molecule anticancer agent that functions by chelating labile inhibitory zinc from procaspase-3, 31 thereby facilitating the autoactivation of procaspase-3 to caspase-3. 28 This mechanism of PAC-1 has been demonstrated in many different ways, 19 including studies examining the timing of apoptotic events, 32,33 and experiments using selective caspase inhibitors 32 and substrates. 34 As a single agent, PAC-1 displays considerable anticancer activity, 19 inducing apoptosis in cell culture and inhibiting tumor growth in murine models, and a derivative demonstrated activity in canine patients with naturally occurring lymphomas.…”

Section: Introductionmentioning

confidence: 99%

Small-Molecule Procaspase-3 Activation Sensitizes Cancer to Treatment with Diverse Chemotherapeutics

et al. 2016

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Conventional chemotherapeutics remain essential treatments for most cancers, but their combination with other anticancer drugs (including targeted therapeutics) is often complicated by unpredictable synergies and multiplicative toxicities. As cytotoxic anticancer chemotherapeutics generally function through induction of apoptosis, we hypothesized that a molecularly targeted small molecule capable of facilitating a central and defining step in the apoptotic cascade, the activation of procaspase-3 to caspase-3, would broadly and predictably enhance activity of cytotoxic drugs. Here we show that procaspase-activating compound 1 (PAC-1) enhances cancer cell death induced by 15 different FDA-approved chemotherapeutics, across many cancer types and chemotherapeutic targets. In particular, the promising combination of PAC-1 and doxorubicin induces a synergistic reduction in tumor burden and enhances survival in murine tumor models of osteosarcoma and lymphoma. This PAC-1/doxorubicin combination was evaluated in 10 pet dogs with naturally occurring metastatic osteosarcoma or lymphoma, eliciting a biologic response in 3 of 6 osteosarcoma patients and 4 of 4 lymphoma patients. Importantly, in both mice and dogs, coadministration of PAC-1 with doxorubicin resulted in no additional toxicity. On the basis of the mode of action of PAC-1 and the high expression of procaspase-3 in many cancers, these results suggest the combination of PAC-1 with cytotoxic anticancer drugs as a potent and general strategy to enhance therapeutic response.

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Derivatives of Procaspase-Activating Compound 1 (PAC-1) and their Anticancer Activities

Cited by 34 publications

References 104 publications

Developing drugs targeting transition metal homeostasis

Developing drugs targeting transition metal homeostasis

Synergistic and targeted therapy with a procaspase-3 activator and temozolomide extends survival in glioma rodent models and is feasible for the treatment of canine malignant glioma patients

Small-Molecule Procaspase-3 Activation Sensitizes Cancer to Treatment with Diverse Chemotherapeutics

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