Cell Death Induction in Cancer Therapy - Past, Present, and Future

Abstract

The induction of apoptosis, a physiological type of cell death, is currently the primary therapeutic aim of most cancer therapies. As resistance to apoptosis is an early hallmark of developing cancer, the success of this treatment strategy is already potentially compromised at treatment initiation. In this review, we discuss the tumor in Darwinian terms and describe it as a complex, yet highly unstable, ecosystem. Current therapeutic strategies often focus on directly killing the dominant subclone within the population of mutated cancer cells while ignoring the subclonal complexity within the ecosystem tumor, the complexity of the direct tumor/ microenvironment interaction and the contribution of the ecosystem human - that is, the global environment which provides the tumor with both support and challenges. The Darwinian view opens new possible therapeutic interventions, such as the disruption of the microenvironment by targeting nonmutated cells within the tumor or the interaction points of mutant tumor cells with their environment, and it forces us to reevaluate therapeutic endpoints. It is our belief that a central future challenge of apoptosis-inducing therapies will be to understand better under which preconditions which treatment strategy and which therapeutic endpoint will lead to the highest quality and quantity of a patient's life.

Interplay between apoptosis and autophagy in colorectal cancer

“…Extrinsic pathway is initiated via the activation of the death receptors. Induction of apoptosis is accepted as the principle aim for most anti-cancer therapies, including chemotherapy, radiotherapy, and immunotherapy [ 6 ].…”

Perspective on the dynamics of cancer

“…In addition, most of the genes and pathways implicated in carcinogenesis have been considered for targeted therapies, including HER/EGFR [ 83 , 84 ], PI3K-AKT-MTOR [ 85 – 87 ], RAS-RAF-ERK [ 88 , 89 ], TGF-β [ 76 , 90 ], AMPK [ 91 – 94 ], the RB pathway [ 95 – 97 ], LDHA [ 75 , 81 , 98 , 99 ], MCT1 [ 100 , 101 ], and NF-χβ/IKK [ 59 , 77 , 102 ]. While the prospect of targeted therapies may be promising [ 103 – 110 ], the specter of acquired disease resistance looms large, representing a persistent challenge to the development of a decisive cancer therapeutic strategy [ 111 – 116 ]. Nevertheless, we speculate that therapies targeting cancer metabolism and TME inflammation might prove effective if combined within a metronomic strategy with the aim to induce a progressive dragging of the CCs-TME dynamics away from tumor promotion and along a staged restoration of tissue homeostasis that avoids the incitement of drug resistance or radical wound repair-like tissue reactions.…”

Cell death-based treatment of childhood cancer

“…Modern cancer therapy is built on three pillars, surgery, radio- and chemotherapy, with a fourth—which actually precedes the latter two—currently gathering momentum: immunotherapy 1 – 3 . Surgery aside, all of these medical approaches are based on the induction of cell death, and they work.…”

“…There are currently more than a dozen forms of cell death recognised. However, the preferred mode by which cell death is therapeutically induced remains a mechanism termed ‘apoptosis’, which also plays a crucial role in normal physiology and was first described more than 40 years ago 1 , 5 . Other forms of cell death that are of therapeutic interest are 'mitotic catastrophe', which is induced by some subgroups of chemotherapeutic reagents, 'autophagic cell death', which is closely related to 'autophagy', a cellular survival mechanism, and the unregulated cell death 'necrosis', which is immunogenic, i.e., causes inflammation and can elicit an immune response of potentially therapeutic value 1 , 6 , 7 .…”

“…The primary aim of cancer therapy has hardly changed since the first recorded cases of treating tumours of the breast 3500 years ago 1 , c aedite eos - eradicating all tumour cells and thereby curing the patient. Only if the primary aim is unachievable, would we consider minimising tumour spread and rate of growth as to achieving maximal quality and quantity of life for the patients.…”