Single-cell transcriptomics identifies Mcl-1 as a target for senolytic therapy in cancer

Troiani, Martina; Colucci, Manuel; D’Ambrosio, Mariantonietta; Guccini, Ilaria; Pasquini, Emiliano; Varesi, Angelica; Valdata, Aurora; Mosole, Simone; Revandkar, Ajinkya; Attanasio, Giuseppe; Rinaldi, Andrea; Rinaldi, Anna Maria; Bolis, Marco; Cippà, Pietro E; Alimonti, Andrea

doi:10.1038/s41467-022-29824-1

Cited by 65 publications

(64 citation statements)

References 93 publications

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“…Recently, scRNA sequencing of prostate cancer cells from Pten pc−/− and Pten pc−/− ; Timp1 −/− mouse models showed Mcl‐1 induction upon senescence. Consistently, the MCL‐1 inhibitors S63845, UMI77 and AZD5991 efficiently eliminated those senescent prostate cancer cells [ 208 ].…”

Section: Senolytics and Other Senotherapeuticsmentioning

confidence: 86%

“…Besides eliminating a wide-range of mouse and human senescent cells, navitoclax (ABT-263), can rejuvenate the hematopoietic system of irradiated mice [162] and ABT-737 selectively eliminated senescent cells in lung and skin [157]. Importantly, in most cell Consistently, the MCL-1 inhibitors S63845, UMI77 and AZD5991 efficiently eliminated those senescent prostate cancer cells [167].…”

Section: Bh3 Mimeticsmentioning

confidence: 99%

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Targeting senescence as an anticancer therapy

Bousset

Gil

2022

Molecular Oncology

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Cellular senescence is a stress response elicited by different molecular insults. Senescence results in cell cycle exit and is characterised by multiple phenotypic changes such as the production of a bioactive secretome. Senescent cells accumulate during ageing and are present in cancerous and fibrotic lesions. Drugs that selectively kill senescent cells (senolytics) have shown great promise for the treatment of age-related diseases. Senescence plays paradoxical roles in cancer. Induction of senescence limits cancer progression and contributes to therapy success, but lingering senescent cells fuel progression, recurrence, and metastasis.In this review, we describe the intricate relation between senescence and cancer. Moreover, we enumerate how current anti-cancer therapies induce senescence in tumour cells and how senolytic agents could be deployed to complement anticancer therapies. "One-two punch" therapies aim to first induce senescence in the tumour followed by senolytic treatment to target newly exposed vulnerabilities in senescent tumour cells. "One-two punch" represents an emerging and promising new strategy in cancer treatment. Future challenges of "one -two punch" approaches include how to best monitor senescence in cancer patients to effectively survey their efficacy.

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Section: Senolytics and Other Senotherapeuticsmentioning

confidence: 86%

Section: Bh3 Mimeticsmentioning

confidence: 99%

Targeting senescence as an anticancer therapy

Bousset

Gil

2022

Molecular Oncology

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“…When prostate cancer cells (PC3 and LNCaP) were treated with docetaxel and palbociclib, they became senescent, and using of S63845, a Mcl-1 inhibitor, reduced the percentage of SA β-gal positive cells. It leads to apoptosis of senescent cells and enhancement of cleaved caspase 3 [ 177 ]. As a result, S6345 can be suggested as another senolytic drug, which targets and inhibits Mcl-1 in PCa cell lines [ 176 , 177 ].…”

Section: Senotherapeuticsmentioning

confidence: 99%

“…It leads to apoptosis of senescent cells and enhancement of cleaved caspase 3 [ 177 ]. As a result, S6345 can be suggested as another senolytic drug, which targets and inhibits Mcl-1 in PCa cell lines [ 176 , 177 ].…”

Section: Senotherapeuticsmentioning

confidence: 99%

Distinct mechanisms mediating therapy-induced cellular senescence in prostate cancer

et al. 2022

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Background Prostate cancer (PCa) is an age-related malignancy in men with a high incidence rate. PCa treatments face many obstacles due to cancer cell resistance and many bypassing mechanisms to escape therapy. According to the intricacy of PCa, many standard therapies are being used depending on PCa stages including radical prostatectomy, radiation therapy, androgen receptor (AR) targeted therapy (androgen deprivation therapy, supraphysiological androgen, and AR antagonists) and chemotherapy. Most of the aforementioned therapies have been implicated to induce cellular senescence. Cellular senescence is defined as a stable cell cycle arrest in the G1 phase and is one of the mechanisms that prevent cancer proliferation. Results In this review, we provide and analyze different mechanisms of therapy-induced senescence (TIS) in PCa and their effects on the tumor. Interestingly, it seems that different molecular pathways are used by cancer cells for TIS. Understanding the complexity and underlying mechanisms of cellular senescence is very critical due to its role in tumorigenesis. The most prevalent analyzed pathways in PCa as TIS are the p53/p21WAF1/CIP1, the p15INK4B/p16INK4A/pRb/E2F/Cyclin D, the ROS/ERK, p27Kip1/CDK/pRb, and the p27Kip1/Skp2/C/EBP β signaling. Despite growth inhibition, senescent cells are highly metabolically active. In addition, their secretome, which is termed senescence-associated secretory phenotype (SASP), affects within the tumor microenvironment neighboring non-tumor and tumor cells and thereby may regulate the growth of tumors. Induction of cancer cell senescence is therefore a double-edged sword that can lead to reduced or enhanced tumor growth. Conclusion Thus, dependent on the type of senescence inducer and the specific senescence-induced cellular pathway, it is useful to develop pathway-specific senolytic compounds to specifically targeting senescent cells in order to evict senescent cells and thereby to reduce SASP side effects.

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“…Other studies suggest that senescent cells being in a non-cycling state, along with increasing levels of CDK inhibition, may alternatively explain their resistance to cell death [ 105 ]. MCL-1 is another member of the BCL-2 family that plays a role in maintaining the survival of senescent cells since its selective inhibition commits these cells to cellular demise [ 106 ]. Another potential explanation of how senescent cells resist cell death is by downregulating the expression of caspase-3, which is responsible for the execution of apoptosis upon the mitochondrial release of cytochrome c and activation of the caspase pathway [ 107 ].…”

Section: Oncogene-induced Senescencementioning

confidence: 99%

Senolytic Therapy: A Potential Approach for the Elimination of Oncogene-Induced Senescent HPV-Positive Cells

Saleh

Khasawneh

Himsawi

et al. 2022

IJMS

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Senescence represents a unique cellular stress response characterized by a stable growth arrest, macromolecular alterations, and wide spectrum changes in gene expression. Classically, senescence is the end-product of progressive telomeric attrition resulting from the repetitive division of somatic cells. In addition, senescent cells accumulate in premalignant lesions, in part, as a product of oncogene hyperactivation, reflecting one element of the tumor suppressive function of senescence. Oncogenic processes that induce senescence include overexpression/hyperactivation of H-Ras, B-Raf, and cyclin E as well as inactivation of PTEN. Oncogenic viruses, such as Human Papilloma Virus (HPV), have also been shown to induce senescence. High-risk strains of HPV drive the immortalization, and hence transformation, of cervical epithelial cells via several mechanisms, but primarily via deregulation of the cell cycle, and possibly, by facilitating escape from senescence. Despite the wide and successful utilization of HPV vaccines in reducing the incidence of cervical cancer, this measure is not effective in preventing cancer development in individuals already positive for HPV. Accordingly, in this commentary, we focus on the potential contribution of oncogene and HPV-induced senescence (OIS) in cervical cancer. We further consider the potential utility of senolytic agents for the elimination of HPV-harboring senescent cells as a strategy for reducing HPV-driven transformation and the risk of cervical cancer development.

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Single-cell transcriptomics identifies Mcl-1 as a target for senolytic therapy in cancer

Cited by 65 publications

References 93 publications

Targeting senescence as an anticancer therapy

Targeting senescence as an anticancer therapy

Distinct mechanisms mediating therapy-induced cellular senescence in prostate cancer

Senolytic Therapy: A Potential Approach for the Elimination of Oncogene-Induced Senescent HPV-Positive Cells

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