Combination of palbociclib with navitoclax based-therapies enhances in vivo antitumoral activity in triple-negative breast cancer

Estepa-Fernández, Alejandra; García‐Fernández, Alba; Lérida-Viso, Araceli; Blandez, Juan F.; Galiana, Irene; Sancenon-Galarza, Félix; Orzáez, Mar; Martínez‐Máñez, Ramón

doi:10.1016/j.phrs.2022.106628

Cited by 15 publications

(10 citation statements)

References 71 publications

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“…Our study used two TNBC cell lines, MDA-MB-231 human breast cancer cells, and 4T1 murine mammary carcinoma cells. In line with previous studies [ 8 , 28 ], 4T1 cells were less sensitive to Pal treatment, while Nif treatment showed no significant difference between the two cell lines [ 17 ]. CDK4/CKD6 expression levels and p21-pRB signaling pathways levels showed no significant differences between the two cells.…”

Section: Discussionsupporting

confidence: 91%

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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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Section: Discussionsupporting

confidence: 91%

“…The anticancer effect of Pal is mainly due to its ability to disrupt the cell cycle process and induce cancer cell senescence [ 6 , 7 ]. Promising clinical advances have encouraged Pal treatment in TNBC patients [ 8 ]. However, TNBC is less sensitive to CDK4/6 inhibition through poorly understood mechanisms.…”

Section: Introductionmentioning

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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“…For instance, Nav‐Gal, the galacto‐conjugant of Navitoclax, was reported to enhance the cytotoxicity of cisplatin in human A549 lung cancer cells, and concomitant treatment with cisplatin and Nav‐Gal eradicated senescent lung cancer cells and significantly reduced tumor growth with reduced Navitoclax‐induced platelet apoptosis 345 . Similar results were obtained in another study of triple‐negative breast cancer (TNBC), in which the combination of palbociclib with Nav‐Gal delayed tumor growth and reduced metastases in an aggressive human TNBC‐derived mouse xenograft model through successful senescence induction and the subsequent removal of senescent cells 346 . These studies offer an efficient strategy of combining senescence induction with senolysis for cancer treatment and provide a targeted approach to develop effective and safer therapeutics.…”

Section: Exploiting Senescence For Cancer Therapysupporting

confidence: 68%

“… 345 Similar results were obtained in another study of triple‐negative breast cancer (TNBC), in which the combination of palbociclib with Nav‐Gal delayed tumor growth and reduced metastases in an aggressive human TNBC‐derived mouse xenograft model through successful senescence induction and the subsequent removal of senescent cells. 346 These studies offer an efficient strategy of combining senescence induction with senolysis for cancer treatment and provide a targeted approach to develop effective and safer therapeutics.…”

Section: Exploiting Senescence For Cancer Therapymentioning

confidence: 99%

Cellular senescence in cancer: molecular mechanisms and therapeutic targets

Jin,

Duan,

et al. 2024

MedComm

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Aging exhibits several hallmarks in common with cancer, such as cellular senescence, dysbiosis, inflammation, genomic instability, and epigenetic changes. In recent decades, research into the role of cellular senescence on tumor progression has received widespread attention. While how senescence limits the course of cancer is well established, senescence has also been found to promote certain malignant phenotypes. The tumor‐promoting effect of senescence is mainly elicited by a senescence‐associated secretory phenotype, which facilitates the interaction of senescent tumor cells with their surroundings. Targeting senescent cells therefore offers a promising technique for cancer therapy. Drugs that pharmacologically restore the normal function of senescent cells or eliminate them would assist in reestablishing homeostasis of cell signaling. Here, we describe cell senescence, its occurrence, phenotype, and impact on tumor biology. A “one‐two‐punch” therapeutic strategy in which cancer cell senescence is first induced, followed by the use of senotherapeutics for eliminating the senescent cells is introduced. The advances in the application of senotherapeutics for targeting senescent cells to assist cancer treatment are outlined, with an emphasis on drug categories, and the strategies for their screening, design, and efficient targeting. This work will foster a thorough comprehension and encourage additional research within this field.

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“…We also validate the efficacy of the NavGa prodrug for TNBC therapy. 57 NavGa effectively eliminates senescent MDA-MB-231 cells (induced with palbociclib) with an improved senolytic index. The NavGa prodrug exhibited lower cytotoxic in nonsenescent MDA-MB-231 cells, thus demonstrating their selective activity in senescent cells.…”

Section: Cellular Senescence Elimination As Therapy: Senotherapiesmentioning

confidence: 98%

Chemical Strategies for the Detection and Elimination of Senescent Cells

García-Fleitas,

García-Fernández,

Martí-Centelles

et al. 2024

Acc. Chem. Res.

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Combination of palbociclib with navitoclax based-therapies enhances in vivo antitumoral activity in triple-negative breast cancer

Cited by 15 publications

References 71 publications

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

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

Cellular senescence in cancer: molecular mechanisms and therapeutic targets

Chemical Strategies for the Detection and Elimination of Senescent Cells

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