The Dark Side of Apoptosis

Shekhar, Malathy P.V.

doi:10.1007/978-1-4614-7070-0_12

Cited by 4 publications

(5 citation statements)

References 58 publications

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“…In 2013, Malathy Shekhar published a comprehensive book chapter entitled "The Dark Side of Apoptosis" in which she discussed accumulating clinical evidence for the paradoxical role of apoptosis in tumor progression [66]. Since then, the oncogenic functions of caspase 3 [17,67,68], together with the ability of cancer cells to return from the brink of apoptotic and other modes of cell death through anastasis [16,17], have all been well established and extensively reviewed (also see Figure 6).…”

Section: Pro-survival Properties Of Cancer Cells Triggered To Undergo...mentioning

confidence: 99%

Intratumor Heterogeneity and Treatment Resistance of Solid Tumors with a Focus on Polyploid/Senescent Giant Cancer Cells (PGCCs)

Mirzayans

Murray

2023

IJMS

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Single cell biology has revealed that solid tumors and tumor-derived cell lines typically contain subpopulations of cancer cells that are readily distinguishable from the bulk of cancer cells by virtue of their enormous size. Such cells with a highly enlarged nucleus, multiple nuclei, and/or multiple micronuclei are often referred to as polyploid giant cancer cells (PGCCs), and may exhibit features of senescence. PGCCs may enter a dormant phase (active sleep) after they are formed, but a subset remain viable, secrete growth promoting factors, and can give rise to therapy resistant and tumor repopulating progeny. Here we will briefly discuss the prevalence and prognostic value of PGCCs across different cancer types, the current understanding of the mechanisms of their formation and fate, and possible reasons why these tumor repopulating “monsters” continue to be ignored in most cancer therapy-related preclinical studies. In addition to PGCCs, other subpopulations of cancer cells within a solid tumor (such as oncogenic caspase 3-activated cancer cells and drug-tolerant persister cancer cells) can also contribute to therapy resistance and pose major challenges to the delivery of cancer therapy.

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Section: Pro-survival Properties Of Cancer Cells Triggered To Undergo...mentioning

confidence: 99%

Intratumor Heterogeneity and Treatment Resistance of Solid Tumors with a Focus on Polyploid/Senescent Giant Cancer Cells (PGCCs)

Mirzayans

Murray

2023

IJMS

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“…Clinical studies reported since the 1990s have revealed that solid tumors with a high apoptotic index tend to have a poor prognosis. The dark side of apoptosis based on clinical outcomes was well documented over a decade ago [ 98 , 99 , 100 ] and has been fairly recently reviewed for colon cancer [ 101 , 102 ] and breast cancer [ 103 , 104 , 105 ].…”

Section: Rethinking Pro-apoptotic Strategies To Combat Solid Tumorsmentioning

confidence: 99%

Changing the Landscape of Solid Tumor Therapy from Apoptosis-Promoting to Apoptosis-Inhibiting Strategies

Mirzayans

2024

CIMB

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The many limitations of implementing anticancer strategies under the term “precision oncology” have been extensively discussed. While some authors propose promising future directions, others are less optimistic and use phrases such as illusion, hype, and false hypotheses. The reality is revealed by practicing clinicians and cancer patients in various online publications, one of which has stated that “in the quest for the next cancer cure, few researchers bother to look back at the graveyard of failed medicines to figure out what went wrong”. The message is clear: Novel therapeutic strategies with catchy names (e.g., synthetic “lethality”) have not fulfilled their promises despite decades of extensive research and clinical trials. The main purpose of this review is to discuss key challenges in solid tumor therapy that surprisingly continue to be overlooked by the Nomenclature Committee on Cell Death (NCCD) and numerous other authors. These challenges include: The impact of chemotherapy-induced genome chaos (e.g., multinucleation) on resistance and relapse, oncogenic function of caspase 3, cancer cell anastasis (recovery from late stages of apoptosis), and pitfalls of ubiquitously used preclinical chemosensitivity assays (e.g., cell “viability” and tumor growth delay studies in live animals) that score such pro-survival responses as “lethal” events. The studies outlined herein underscore the need for new directions in the management of solid tumors.

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“…As it turned out, we were wrong! In a comprehensive book chapter entitled "The Dark Side of Apoptosis" published in 2013 [22], Malathy Shekhar discussed accumulating evidence for the paradoxical role of apoptosis in tumor progression. In breast cancer, for example, BCL2 overexpression was already (over a decade ago) known to be associated with "normal ploidy, estrogen receptor positivity, and absence of metastasis; all characteristics associated with better clinical outcome and a more favorable prognosis that is contradictory to its (BCL2's) predicted role in apoptosis resistance" [22].…”

Section: Introductionmentioning

confidence: 99%

“…In a comprehensive book chapter entitled "The Dark Side of Apoptosis" published in 2013 [22], Malathy Shekhar discussed accumulating evidence for the paradoxical role of apoptosis in tumor progression. In breast cancer, for example, BCL2 overexpression was already (over a decade ago) known to be associated with "normal ploidy, estrogen receptor positivity, and absence of metastasis; all characteristics associated with better clinical outcome and a more favorable prognosis that is contradictory to its (BCL2's) predicted role in apoptosis resistance" [22]. As pointed out by this author [22] and others (e.g., [23][24][25][26]), numerous clinical studies published since the mid-1990s have shown that patients with high rates of apoptosis had significantly worse prognosis compared to patients with low apoptotic rates; the study reported by Yang et al in 2018 [26] involved a meta-analysis of 3091 breast cancer cases.…”

Section: Introductionmentioning

confidence: 99%

When Therapy-Induced Cancer Cell Apoptosis Fuels Tumor Relapse

Mirzayans

2024

Onco

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Most therapeutic strategies for solid tumor malignancies are designed based on the hypothesis that cancer cells evade apoptosis to exhibit therapy resistance. This is somewhat surprising given that clinical studies published since the 1990s have demonstrated that increased apoptosis in solid tumors is associated with cancer aggressiveness and poor clinical outcome. This is consistent with more recent reports demonstrating non-canonical (pro-survival) roles for apoptotic caspases, including caspase 3, as well as the ability of cancer cells to recover from late stages of apoptosis via a process called anastasis. These activities are essential for the normal development and maintenance of a healthy organism, but they also enable malignant cells (including cancer stem cells) to resist anticancer treatment and potentially contribute to clinical dormancy (minimal residual disease). Like apoptosis, therapy-induced cancer cell dormancy (durable proliferation arrest reflecting various manifestations of genome chaos) is also not obligatorily a permanent cell fate. However, as briefly discussed herein, compelling pre-clinical studies suggest that (reversible) dormancy might be the “lesser evil” compared to treacherous apoptosis.

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The Dark Side of Apoptosis

Cited by 4 publications

References 58 publications

Intratumor Heterogeneity and Treatment Resistance of Solid Tumors with a Focus on Polyploid/Senescent Giant Cancer Cells (PGCCs)

Intratumor Heterogeneity and Treatment Resistance of Solid Tumors with a Focus on Polyploid/Senescent Giant Cancer Cells (PGCCs)

Changing the Landscape of Solid Tumor Therapy from Apoptosis-Promoting to Apoptosis-Inhibiting Strategies

When Therapy-Induced Cancer Cell Apoptosis Fuels Tumor Relapse

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