Indisulam synergizes with palbociclib to induce senescence through inhibition of CDK2 kinase activity

Pogacar, Ziva; Johnson, Jackie; Krenning, Lenno; Conti, Giulia De; Jochems, Fleur; Lieftink, Cor; Velds, Arno; Wardak, Leyma; Groot, K. de; Schepers, Arnout; Wang, Liqin; Song, Ji‐Ying; Ven, Marieke van de; Tellingen, Olaf van; Medema, René H.; Beijersbergen, Roderick L.; Bernards, René; Oliveira, Rodrigo Leite de

doi:10.1371/journal.pone.0273182

Cited by 11 publications

(8 citation statements)

References 65 publications

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“…Similar results were generated by Pogacar et al. ( 180 ), using the CDK2 inhibitor, indisulam, in triple-negative breast cancer, where the combination of palbociclib and indisulam resulted in sustained senescence induction.…”

Section: Senescence and Breast Cancer Cell Survivalsupporting

confidence: 85%

Autophagy and senescence facilitate the development of antiestrogen resistance in ER positive breast cancer

McGrath,

Abolhassani,

Guy

et al. 2024

Front. Endocrinol.

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Estrogen receptor positive (ER+) breast cancer is the most common breast cancer diagnosed annually in the US with endocrine-based therapy as standard-of-care for this breast cancer subtype. Endocrine therapy includes treatment with antiestrogens, such as selective estrogen receptor modulators (SERMs), selective estrogen receptor downregulators (SERDs), and aromatase inhibitors (AIs). Despite the appreciable remission achievable with these treatments, a substantial cohort of women will experience primary tumor recurrence, subsequent metastasis, and eventual death due to their disease. In these cases, the breast cancer cells have become resistant to endocrine therapy, with endocrine resistance identified as the major obstacle to the medical oncologist and patient. To combat the development of endocrine resistance, the treatment options for ER+, HER2 negative breast cancer now include CDK4/6 inhibitors used as adjuvants to antiestrogen treatment. In addition to the dysregulated activity of CDK4/6, a plethora of genetic and biochemical mechanisms have been identified that contribute to endocrine resistance. These mechanisms, which have been identified by lab-based studies utilizing appropriate cell and animal models of breast cancer, and by clinical studies in which gene expression profiles identify candidate endocrine resistance genes, are the subject of this review. In addition, we will discuss molecular targeting strategies now utilized in conjunction with endocrine therapy to combat the development of resistance or target resistant breast cancer cells. Of approaches currently being explored to improve endocrine treatment efficacy and patient outcome, two adaptive cell survival mechanisms, autophagy, and “reversible” senescence, are considered molecular targets. Autophagy and/or senescence induction have been identified in response to most antiestrogen treatments currently being used for the treatment of ER+ breast cancer and are often induced in response to CDK4/6 inhibitors. Unfortunately, effective strategies to target these cell survival pathways have not yet been successfully developed. Thus, there is an urgent need for the continued interrogation of autophagy and “reversible” senescence in clinically relevant breast cancer models with the long-term goal of identifying new molecular targets for improved treatment of ER+ breast cancer.

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Section: Senescence and Breast Cancer Cell Survivalsupporting

confidence: 85%

Autophagy and senescence facilitate the development of antiestrogen resistance in ER positive breast cancer

McGrath,

Abolhassani,

Guy

et al. 2024

Front. Endocrinol.

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“…To clarify the mechanism of action of the selected 6-Amino-SPD and 6-Morpholino-SPD derivatives and their inhibitory effects on leukemia cells, further research focused on confirming their anti-apoptotic effects. As previously mentioned, these derivatives have shown potent effect in the accumulation of leukemia cells in subG0 phase [ 19 ], indicating apoptosis characterized by fragmented DNA [ 26 , 27 ]. The results of this study show that both 6-Amino-SPD and 6-Morpholino-SPD derivatives induce apoptosis in the K562 cell line ( Figure 2 ).…”

Section: Discussionmentioning

confidence: 99%

“…These findings are consistent with the results of previously published studies investigating compounds with similar structures. It is worth noting that indisulam, which belongs to the sulfonamide class, has anticancer activity through several mechanisms [ 27 , 28 , 29 ]. These include inhibition of carbonic anhydrase, affecting various cell cycle checkpoints, and inducing apoptosis by affecting apoptotic Bax/Bcl2 proteins.…”

Section: Discussionmentioning

confidence: 99%

The Mechanism of Anti-Tumor Activity of 6-Morpholino- and 6-Amino-9-Sulfonylpurine Derivatives on Human Leukemia Cells

Leventić,

Opačak-Bernardi,

Rastija

et al. 2023

Molecules

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The aim of this study was to explore the mechanism of antitumor effect of (E)-6-morpholino-9-(styrylsulfonyl)-9H-purine (6-Morpholino-SPD) and (E)-6-amino-9-(styrylsulfonyl)-9H-purine (6-Amino-SPD). The effects on apoptosis induction, mitochondrial potential, and accumulation of ROS in treated K562 cells were determined by flow cytometry. The RT-PCR method was used to measure the expression of Akt, CA IX, caspase 3, and cytochrome c genes, as well as selected miRNAs. Western blot analysis was used to determine the expression of Akt, cytochrome c, and caspase 3. The results demonstrate the potential of the tested derivatives as effective antitumor agents with apoptotic-inducing properties. In leukemic cells treated with 6-Amino-SPD, increased expression of caspase 3 and cytochrome c genes was observed, indicating involvement of the intrinsic mitochondrial pathway in the induction of apoptosis. Conversely, leukemic cells treated with 6-Morpholino-SPD showed reduced expression of these genes. The observed downregulation of miR-21 by 6-Morpholino-SPD may contribute to the induction of apoptosis and disruption of mitochondrial function. In addition, both derivatives exhibited increased expression of Akt and CA IX genes, suggesting activation of the Akt/HIF pathway. However, the exact mechanism and its relations to the observed overexpression of miR-210 need further investigation. The acceptable absorption and distribution properties predicted by ADMET analysis suggest favorable pharmacokinetic properties for these derivatives.

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“…Stable CDK2-shRNA knockdown cells were generated as described previously [ 38 ]. CDK2 shRNA (5‘-CTCCTGGGCTGCAAATATTAT-3‘) was constructed by Beyotime Biotechnology (Shanghai, China).…”

Section: Methodsmentioning

confidence: 99%

Nifuroxazide boosts the anticancer efficacy of palbociclib-induced senescence by dual inhibition of STAT3 and CDK2 in triple-negative breast cancer

Wang,

Shi,

Wang

et al. 2023

Cell Death Discov.

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Though palbociclib, a cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor has been approved for treating breast cancer, two major clinical challenges remain: (i) Triple-negative breast cancer (TNBC) appears to be more resistant to palbociclib, and (ii) Palbociclib-induced senescence-associated secretory phenotype (SASP) has a pro-tumorigenic function. Here we report that combining palbociclib with the STAT3 inhibitor nifuroxazide uncouples SASP production from senescence-associated cell cycle exit. Moreover, we identified nifuroxazide as a CDK2 inhibitor that synergistically promotes palbociclib-induced growth arrest and senescence in TNBC cells. In vitro, the combination of nifuroxazide with palbociclib further inhibited the TNBC cell proliferation and enhanced palbociclib-induced cell cycle arrest and senescence. The modulation of palbociclib-induced SASP by nifuroxazide was associated with the reduction of phosphorylated-STAT3. Nifuroxazide also blocks SASP-dependent cancer cell migration. Furthermore, thermal shift assay and molecular docking of nifuroxazide with STAT3 and CDK2 revealed that it binds to their active sites and acts as a potent dual inhibitor. In vivo, the combination of nifuroxazide with palbociclib suppressed 4T1 tumor growth and lung metastasis. Our data suggest that nifuroxazide enhances the anticancer effects of palbociclib in TNBC by uncoupling SASP production from senescence-associated cell cycle exit and inhibiting CDK2 to promote tumor senescence.

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Indisulam synergizes with palbociclib to induce senescence through inhibition of CDK2 kinase activity

Cited by 11 publications

References 65 publications

Autophagy and senescence facilitate the development of antiestrogen resistance in ER positive breast cancer

Autophagy and senescence facilitate the development of antiestrogen resistance in ER positive breast cancer

The Mechanism of Anti-Tumor Activity of 6-Morpholino- and 6-Amino-9-Sulfonylpurine Derivatives on Human Leukemia Cells

Nifuroxazide boosts the anticancer efficacy of palbociclib-induced senescence by dual inhibition of STAT3 and CDK2 in triple-negative breast cancer

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