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

Abstract

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.

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

“…Importantly, human and canine astrocytomas and gliomas present with similar morphologies, pathologies and molecular abnormalities [ 37 – 39 ]. The pharmacokinetics and efficacy of PAC-1/derivatives has been well studied in pet dogs with cancer, including those with lymphoma and metastatic osteosarcoma [ 26 , 40 , 41 ]. Prior to initiating a feasibility study of PAC-1 in pet dogs with brain cancer, the suitability of PAC-1 targeted therapy for canine glioma was determined using a small cohort (n = 4) of archived paraffin-embedded tumor samples.…”

“…By relieving the physiologic labile zinc inhibition of procaspase-3, PAC-1 is able to enhance the ability of procaspase-3 to undergo auto-activation, sensitize the cellular procaspase-3 population to upstream apoptotic signaling events, and enhance the activity of caspase-3 generated through the induction of apoptosis [ 22 , 26 ]. In recent reports PAC-1 has demonstrated dramatic synergy with a number of anticancer agents [ 27 ], most notably with doxorubicin for the treatment of metastatic osteosarcoma [ 26 ], and with vemurafenib for the treatment of mutant BRAF melanoma [ 28 ].…”

Companion canines: an under-utilised model to aid in translating anti-metastatics to the clinic

“…However, it also may potentiate other therapies. A PAC-1/doxorubicin combination treatment lead to a biologic response in 3/6 dogs with metastatic OSA, and 4/4 dogs with lymphoma [26], whilst a PAC-1/ temozolomide (TMZ) combination achieved biological responses in 3/3 dogs with glioma [27]. Although there are trials at different Institutes within the USA that are currently recruiting canines with lung metastatic OSA to further assess the effectiveness of the PAC-1/doxorubicin combination, Phase I clinical trials using the PAC-1/TMZ combination in humans with high grade gliomas (glioblastoma multiforme or anaplastic astrocytoma after progression following standard first line therapy) have already begun (ClinicalTrials.…”

Of Mice, Dogs, Pigs, and Men: Choosing the Appropriate Model for Immuno-Oncology Research

“…In addition to mifamurtide, other investigational agents that included pet dogs with cancer in the pathway towards investigational new drug designation and human Phase I clinical trials include GS-9219, KPT-335, and PAC-1. 107,[201][202][203][204][205] Given the immune competency of pet dogs with cancer, and underscoring the unique and valuable potential of large animal models in cancer research, the NCI recently launched a request for proposals to support canine clinical studies evaluating the feasibility and activity of immunotherapeutic agents and novel drug combinations such as immune modulators, molecular targeted agents, chemotherapy, and/or radiation. 206 Clinical studies will be accompanied by laboratory correlative studies that seek to describe, characterize, and understand the cellular and molecular mechanisms that determine the antitumor response (or lack of response) in dogs with spontaneous tumors.…”