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Cdk7, the CDK-activating kinase and transcription factor IIH component, is a target of inhibitors that kill cancer cells by exploiting tumor-specific transcriptional dependencies. However, whereas selective inhibition of analog-sensitive (AS) Cdk7 in colon cancer-derived cells arrests division and disrupts transcription, it does not by itself trigg...
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Context 1
... cells treated with 5 μM nutlin-3 + 2.5 μM 3-MB-PP1, or with 375 μM 5-FU alone, PARP cleavage measured at 24 hr was largely but not completely prevented if drugs were removed as late as 12 hr after addition. In contrast, combined treatment with 40 μM 5-FU and 2.5 μM 3-MB-PP1 accelerated passage of a point of no return; cells became irreversibly committed to apoptosis 6-9 hr after drug addition ( Figure 5A). Nutlin-3 acts directly to inhibit ubiquitylation and proteasomal degradation of p53 ( Vassilev et al., 2004). ...
Context 2
... mechanism of 5-FU action is indirect, requiring a toxic intermediate that, once it accumulates, can sustain p53 activation in the absence of the drug. Consistent with this scenario, we achieved similar cell-killing efficacy by simultaneous or sequential treatment with 5-FU and 3-MB-PP1, whereas nutlin-3 and 3-MB-PP1 needed to be administered together ( Figure 5B). Moreover, the lethality of sequential treatment depended on the order of drug addition: 3-MB-PP1 was equally effective whether it was given with or after 5-FU treatment, and either regimen was more effective than 5-FU given only after 3- MB-PP1 removal. ...
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... of 1 μM triptolide during the first (5-FU) or second (3-MB-PP1) treatment suppressed PARP cleavage ( Figure 5C). Rescue by triptolide after removal of 5-FU indicates that ongoing Pol II transcription is required to activate caspases when Cdk7 is inhibited. ...
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... together with the relative toxicities of 5-FUR and 5-FUdR ( Figure 4B, C), the results suggest that transcription is needed for both steps in the pathway leading to cell death, with a specific requirement for Pol II at the second, 3-MB-PP1-dependent step. Moreover, a time course of 3-MB-PP1 treatment after 5-FU washout indicated that the relevant differences in gene expression caused by Cdk7 inhibition would be detectable by 3-6 hr after addition of 3-MB-PP1, when cells have committed to apoptosis but before effector caspases are activated ( Figure 5D). ...
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... of p53 targets was significantly elevated upon 5-FU treatment in comparison to changes in global mRNA levels ( Figure 6D top panel, 6E top panel). Addition of 3-MB-PP1 to 5-FU-treated cells blunted induction of p53 targets relative to 5-FU treatment alone ( Figure 6B right column, 6D bottom panel, 6E bottom panel), although it did not restore expression of these genes to their pre-5-FU levels ( Figure 6B middle column, Figure S5A-C). Expression of p53-regulated genes such as p21 and MDM2 was reduced, suggesting attenuation of pro-survival transcriptional signaling induced by 40 μM 5-FU ( Figure 6F). ...
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... of p53-regulated genes such as p21 and MDM2 was reduced, suggesting attenuation of pro-survival transcriptional signaling induced by 40 μM 5-FU ( Figure 6F). We validated the decrease in MDM2 transcripts by RT- qPCR analysis of cells treated simultaneously with 3-MB-PP1 and 5-FU ( Figure 6G) or nutlin-3 ( Figure 6H), and verified that this change was dependent on the CDK7 as mutation (i.e., it did not occur in wild-type HCT116 cells, Figure S5D, E). Expression of Mdm2 and p21 proteins was also attenuated by Cdk7 inhibition, in response to sequential treatment with 5-FU and 3-MB-PP1 ( Figures 6I and S5F), or simultaneous treatment with nutlin-3 and 3-MB-PP1 ( Figures 6J and S5G). ...
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... validated the decrease in MDM2 transcripts by RT- qPCR analysis of cells treated simultaneously with 3-MB-PP1 and 5-FU ( Figure 6G) or nutlin-3 ( Figure 6H), and verified that this change was dependent on the CDK7 as mutation (i.e., it did not occur in wild-type HCT116 cells, Figure S5D, E). Expression of Mdm2 and p21 proteins was also attenuated by Cdk7 inhibition, in response to sequential treatment with 5-FU and 3-MB-PP1 ( Figures 6I and S5F), or simultaneous treatment with nutlin-3 and 3-MB-PP1 ( Figures 6J and S5G). ...
Context 8
... validated the decrease in MDM2 transcripts by RT- qPCR analysis of cells treated simultaneously with 3-MB-PP1 and 5-FU ( Figure 6G) or nutlin-3 ( Figure 6H), and verified that this change was dependent on the CDK7 as mutation (i.e., it did not occur in wild-type HCT116 cells, Figure S5D, E). Expression of Mdm2 and p21 proteins was also attenuated by Cdk7 inhibition, in response to sequential treatment with 5-FU and 3-MB-PP1 ( Figures 6I and S5F), or simultaneous treatment with nutlin-3 and 3-MB-PP1 ( Figures 6J and S5G). ...
Context 9
... and FAS proteins were also induced to similar levels by 5-FU or nutlin-3 in the absence or presence of 3-MB-PP1 ( Figures 6I, J and S5F, G). In cells pre-treated with DMSO, 3-MB-PP1 did not selectively affect expression of p53-regulated genes, indicating that it specifically modulated transcriptional responses to p53 stabilization ( Figure S5A-C). These results suggest that Cdk7 inhibitors might synergize with 5-FU or nutlin-3 by tipping the balance of p53-dependent transcription towards death-promoting targets such as DR5 and FAS. ...
Citations
... This finding may explain the increase in p53 and cleaved caspase-7 levels detected in the RPPA data in the presence of WT-ER and mutant ER cell (Fig. 1D). In keeping with these findings, previous reports in other cancer types have highlighted the role of CDK7 inhibition in mediating p53-induced apoptosis [47][48][49][50] . In support of the association between CDK7 and p53, as shown in figure 1C, T47D cells that harbor a pathogenic TP53 mutation (L194F) 51 were less sensitive to SY-1365 compared to MCF7 cells. ...
Purpose
Resistance to endocrine therapy (ET) and CDK4/6 inhibitors (CDK4/6i) is a clinical challenge in estrogen receptor (ER)-positive (ER+) breast cancer. Cyclin-dependent kinase 7 (CDK7) is a candidate target in endocrine-resistant ER+ breast cancer models and selective CDK7 inhibitors (CDK7i) are in clinical development for the treatment of ER+ breast cancer. Nonetheless, the precise mechanisms responsible for the activity of CDK7i in ER+ breast cancer remain elusive. Herein, we sought to unravel these mechanisms.
Experimental Design
We conducted multi-omic analyses in ER+ breast cancer models in vitro and in vivo, including models with different genetic backgrounds. We also performed genome-wide CRISPR/Cas9 knockout screens to identify potential therapeutic vulnerabilities in CDK4/6i-resistant models.
Results
We found that the on-target antitumor effects of CDK7 inhibition in ER+ breast cancer are in part p53 dependent, and involve cell cycle inhibition and suppression of c-Myc. Moreover, CDK7 inhibition exhibited cytotoxic effects, distinctive from the cytostatic nature of ET and CDK4/6i. CDK7 inhibition resulted in suppression of ER phosphorylation at S118; however, long-term CDK7 inhibition resulted in increased ER signaling, supporting the combination of ET with a CDK7i. Finally, genome-wide CRISPR/Cas9 knockout screens identified CDK7 and MYC signaling as putative vulnerabilities in CDK4/6i resistance, and CDK7 inhibition effectively inhibited CDK4/6i-resistant models.
Conclusions
Taken together, these findings support the clinical investigation of selective CDK7 inhibition combined with ET to overcome treatment resistance in ER+ breast cancer. In addition, our study highlights the potential of increased c-Myc activity and intact p53 as predictors of sensitivity to CDK7i-based treatments.
... Subsequently, samuraciclib with fulvestrant showed a 24-week CBR of 36% in a single-arm study of 31 patients with HR + /HER2− ABC post progression on AI plus CDK4/6i, leading to FDA granting fast-track status for the compound 129 . Interestingly, tumors with TP53 mutation have a significantly shorter mPFS than tumors with wild-type TP53 (HR 0.17, P = 0.0008), consistent with findings that TP53 activation is essential to induce transcriptional dependency, rendering the cancer cells susceptible to CDK7 inhibition 130 . Hence there may be limitations with CDK7 inhibitors in aggressive luminal tumors that harbor TP53 alterations. ...
Endocrine therapy (ET) with cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) is currently the standard first-line treatment for most patients with hormone receptor (HR) positive, human epidermal growth factor receptor (HER2) negative advanced breast cancer. However, resistance to ET and CDK4/6i inevitably ensues. The optimal post-progression treatment regimens and their sequencing continue to evolve in the rapidly changing treatment landscape. In this review, we summarize the mechanisms of resistance to ET and CDK4/6i, which can be broadly classified as alterations affecting cell cycle mediators and activation of alternative signaling pathways. Recent clinical trials have been directed at the targets and pathways implicated, including estrogen and androgen receptors, PI3K/AKT/mTOR and MAPK pathways, tyrosine kinase receptors such as FGFR and HER2, homologous recombination repair pathway, other components of the cell cycle and cell death. We describe the findings from these clinical trials using small molecule inhibitors, antibody–drug conjugates and immunotherapy, providing insights into how these novel strategies may circumvent treatment resistance, and discuss how some have not translated into clinical benefit. The challenges posed by tumor heterogeneity, adaptive rewiring of signaling pathways and dose-limiting toxicities underscore the need to elucidate the latest tumor biology in each patient, and develop treatments with improved therapeutic index in the era of precision medicine.
... The highly metastatic PC3 cell line, which does not express p53 protein, appears resistant to apoptosis in response to CT7001 treatment. In addition, activation of p53 transcriptional programme has been demonstrated to sensitise some cancer cells to CDK7 inhibition by promoting pro-apoptotic pathways [57]. As the p53 tumour suppressor is frequently mutated in prostate cancer and has prognostic significance [4,58], future studies should explore whether enhanced sensitivity or/and induction of apoptosis in response to CT7001 treatment is dependent on an intact p53 pathway. ...
Background:
Current strategies to inhibit androgen receptor (AR) are circumvented in castration-resistant prostate cancer (CRPC). Cyclin-dependent kinase 7 (CDK7) promotes AR signalling, in addition to established roles in cell cycle and global transcription, providing a rationale for its therapeutic targeting in CRPC.
Methods:
The antitumour activity of CT7001, an orally bioavailable CDK7 inhibitor, was investigated across CRPC models in vitro and in xenograft models in vivo. Cell-based assays and transcriptomic analyses of treated xenografts were employed to investigate the mechanisms driving CT7001 activity, alone and in combination with the antiandrogen enzalutamide.
Results:
CT7001 selectively engages with CDK7 in prostate cancer cells, causing inhibition of proliferation and cell cycle arrest. Activation of p53, induction of apoptosis, and suppression of transcription mediated by full-length and constitutively active AR splice variants contribute to antitumour efficacy in vitro. Oral administration of CT7001 represses growth of CRPC xenografts and significantly augments growth inhibition achieved by enzalutamide. Transcriptome analyses of treated xenografts indicate cell cycle and AR inhibition as the mode of action of CT7001 in vivo.
Conclusions:
This study supports CDK7 inhibition as a strategy to target deregulated cell proliferation and demonstrates CT7001 is a promising CRPC therapeutic, alone or in combination with AR-targeting compounds.
... It was hybridized with a pyrrolidinopyrazole core from the known PAK4 inhibitor PF-3758309 (10), which impacts CDK7 as an off-target [50,51]. The hybridization led to YKL-1-116 (11) [52], which retained the potent inhibition of CDK7 (IC 50 = 7.6 nM) but suboptimal antiproliferative activity in cells. Further optimization of the linker length between the aminopyrazole core and covalent warhead resulted in YKL-5-124 (12), with similar potency against CDK7 (IC 50 = 9.7 nM), but higher potency against cancer cells [34]. ...
... Combinations of several drugs are often used and have been shown to be beneficial in cancer treatment.To date, CDK7 inhibitors have shown in vitro and in vivo synergistic effect in combination with BH3 mimetics [9,40], BET inhibitors [67], antiestrogens [10,58], p53-activating agents [52] and immunotherapy [19,20]. This strategy has also been tested in the clinical trials particularly for samuraciclib, SY-1365 and SY-5609. ...
Introduction:
Cyclin-dependent kinase 7 (CDK7) is a member of the CDK family of serine/threonine protein kinases and participates in the regulation of the cell cycle and mRNA transcription. CDK7 is emerging as a possible drug target in oncology and six exciting drug candidates have already undergone early evaluation in clinical trials.
Areas covered:
This review examines CDK7 inhibitors as anticancer drugs reported in patents published in the online databases of the World Intellectual Property Organization and European Patent Office in the 2018-2022 period. This review provides an overview of available inhibitors, including their chemical structures, biochemical profile and stage of development.
Expert opinion:
Small-molecule CDK7 inhibitors represent attractive pharmacological modalities for the treatment of various cancer types. Highly potent and selective inhibitors have been discovered and many of them show promising results in several of preclinical cancer models. Developed compounds act on the kinase by various mechanisms, including traditional ATP competition, irreversible binding to tractable cysteine 312 outside the active site of CDK7, and induced protein degradation by proteolysis targeting chimeras. Ongoing preclinical research and clinical trials should reveal which strategy will provide the highest benefits.
... However, co-administration of THZ531 or NVP-2 sensitized HCT116 cells to CDK7 inhibition in a p53-dependent manner ( Figure 6A, B). That p53 enables the death of CDK7 and CDK12 co-targeted cells is consistent with a previous report demonstrating that activation of the p53 transcriptional program sensitized cancer cells to CDK7 inhibitors (77). Figure S6A, B). ...
P-TEFb and CDK12 facilitate transcription elongation by RNA polymerase II and play prominent roles in cancer. Understanding their functional interplay in cancer cells could inform novel therapeutic strategies. While inhibition of CDK12 downregulates unique sets of genes, which elicits genomic instability that is being exploited therapeutically, little is known about the significance of transcriptional induction in CDK12-targeted cells. We show that inhibition of CDK12 in colon cancer-derived cells activates P-TEFb and induces genes of key cancer signaling pathways, including p53 and NF-kappaB. As a result, cancer cells become exquisitely dependent on P-TEFb. Mechanistically, inhibition of P-TEFb ablates the induction of model genes and synergizes with CDK12 inhibitors in cancer cell elimination through activation of p53-dependent apoptosis and attenuation of NF-kappa-dependent proliferation. Furthermore, we show that the DNA damage-responsive ATM kinase mediates these effects. While ATM is required for the synthetic lethality of CDK12 and P-TEFb co-targeting in p53-proficient cells, co-inhibition of ATM and CDK12 synergistically decreases viability of p53-deficient cells. Finally, pairwise targeting of CDK12, P-TEFb and transcription initiation kinase CDK7 stimulates p53-dependent apoptosis of cancer cell spheroids. We propose that the DNA damage-induced stimulation of Pol II pause release by P-TEFb at the signal-responsive genes underlies the dependence of CDK12-targeted cancer cells on P-TEFb. Together, our study provides a rationale for combinatorial targeting of CDK12 and P-TEFb or the induced oncogenic pathways in cancer.
... Of note, cytotoxic effect of selective P-TEFb antagonists alone and in combination with p53 activators was biphasic ( Figure 1C-E and Supplementary Figure S1E), suggesting that high doses of the antagonists lead to transcriptional shutdown that is incompatible with cell death. The biphasic response is reminiscent to the one effectuated by a pan-CDK inhibitor flavopiridol (53), which at high doses attenuates Pol II transcription globally (54,55). ...
... Importantly, Nutlin-3a treatment elicited robust synthetic lethality only with the inhibitor of CDK7, reaching the highest Bliss score of 44 (Supplementary Fig-ure S1H-K). This finding is consistent with a previous study which employed a chemical genetic approach as well as YKL-1-116, a precursor to YKL-5-124, to inhibit CDK7 in a selective manner (53). Interestingly, unlike P-TEFb antagonists, CDK7 inhibitors alone or together with Nutlin-3a and 5-FU continued to elicit cytotoxicity at higher doses (Supplementary Figure S1H) (53), which could reflect the reported lack of global downregulation of Pol II transcriptome upon CDK7 inhibition (53,56). ...
... This finding is consistent with a previous study which employed a chemical genetic approach as well as YKL-1-116, a precursor to YKL-5-124, to inhibit CDK7 in a selective manner (53). Interestingly, unlike P-TEFb antagonists, CDK7 inhibitors alone or together with Nutlin-3a and 5-FU continued to elicit cytotoxicity at higher doses (Supplementary Figure S1H) (53), which could reflect the reported lack of global downregulation of Pol II transcriptome upon CDK7 inhibition (53,56). Nevertheless, CDK7 inhibitors elicited highly synergistic cell death with p53 activators over a relatively narrow range ( Supplementary Figure S1H) (53), which is similar to our results with P-TEFb antagonists. ...
Positive transcription elongation factor b (P-TEFb) is the crucial player in RNA polymerase II (Pol II) pause release that has emerged as a promising target in cancer. Because single-agent therapy may fail to deliver durable clinical response, targeting of P-TEFb shall benefit when deployed as a combination therapy. We screened a comprehensive oncology library and identified clinically relevant antimetabolites and Mouse double minute 2 homolog (MDM2) inhibitors as top compounds eliciting p53-dependent death of colorectal cancer cells in synergy with selective inhibitors of P-TEFb. While the targeting of P-TEFb augments apoptosis by anti-metabolite 5-fluorouracil, it switches the fate of cancer cells by the non-genotoxic MDM2 inhibitor Nutlin-3a from cell-cycle arrest to apoptosis. Mechanistically, the fate switching is enabled by the induction of p53-dependent pro-apoptotic genes and repression of P-TEFb-dependent pro-survival genes of the PI3K-AKT signaling cascade, which stimulates caspase 9 and intrinsic apoptosis pathway in BAX/BAK-dependent manner. Finally, combination treatments trigger apoptosis of cancer cell spheroids. Together, co-targeting of P-TEFb and suppressors of intrinsic apoptosis could become a viable strategy to eliminate cancer cells.
... Indeed, flavopiridol, being nonselective, and dinaciclib, with moderate selectivity, have shown CDK7 inhibition [21]. As CDK7 regulates the proximal-promoter pause of all POLIIregulated genes, systemic inhibition is an undesirable side-effect [63]. Additionally, the tolerability of these compounds varies, with dinaciclib having shown to be associated with weight loss in vivo [21,64]. ...
Chronic lymphocytic leukemia (CLL) is effectively treated with targeted therapies including Bruton tyrosine kinase inhibitors and BCL2 antagonists. When these become ineffective, treatment options are limited. Positive transcription elongation factor complex (P-TEFb), a heterodimeric protein complex composed of cyclin dependent kinase 9 (CDK9) and cyclin T1, functions to regulate short half-life transcripts by phosphorylation of RNA Polymerase II (POLII). These transcripts are frequently dysregulated in hematologic malignancies; however, therapies targeting inhibition of P-TEFb have not yet achieved approval for cancer treatment. VIP152 kinome profiling revealed CDK9 as the main enzyme inhibited at 100 nM, with over a 10-fold increase in potency compared with other inhibitors currently in development for this target. VIP152 induced cell death in CLL cell lines and primary patient samples. Transcriptome analysis revealed inhibition of RNA degradation through the AU-Rich Element (ARE) dysregulation. Mechanistically, VIP152 inhibits the assembly of P-TEFb onto the transcription machinery and disturbs binding partners. Finally, immune competent mice engrafted with CLL-like cells of Eµ-MTCP1 over-expressing mice and treated with VIP152 demonstrated reduced disease burden and improvement in overall survival compared to vehicle-treated mice. These data suggest that VIP152 is a highly selective inhibitor of CDK9 that represents an attractive new therapy for CLL.
... However, p53 activation induced by the MDM2 inhibitor Nutlin and 5-FU increases dependency of p53-dependent transcription by CDK7. CDK7 inhibition shifts the balance from pro-survival to pro-apoptotic transcription of p53 targets [102]. This combination therapy is therefore not effective in p53-deficient cells. ...
Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer defined by lack of the estrogen, progesterone and human epidermal growth factor receptor 2. Although TNBC tumors contain a wide variety of oncogenic mutations and copy number alterations, the direct targeting of these alterations has failed to substantially improve therapeutic efficacy. This efficacy is strongly limited by interpatient and intratumor heterogeneity, and thereby a lack in uniformity of targetable drivers. Most of these genetic abnormalities eventually drive specific transcriptional programs, which may be a general underlying vulnerability. Currently, there are multiple selective inhibitors, which target the transcriptional machinery through transcriptional cyclin-dependent kinases (CDKs) 7, 8, 9, 12 and 13 and bromodomain extra-terminal motif (BET) proteins, including BRD4. In this review, we discuss how inhibitors of the transcriptional machinery can effectively target genetic abnormalities in TNBC, and how these abnormalities can influence sensitivity to these inhibitors. These inhibitors target the genomic landscape in TNBC by specifically suppressing MYC-driven transcription, inducing further DNA damage, improving anti-cancer immunity, and preventing drug resistance against MAPK and PI3K-targeted therapies. Because the transcriptional machinery enables transcription and propagation of multiple cancer drivers, it may be a promising target for (combination) treatment, especially of heterogeneous malignancies, including TNBC.
... Nutlin-3 is a small-molecule MDM2 inhibitor that interferes with MDM2 and p53 binding. By occupying the p53-binding pocket of MDM2, nutlin-3 decreases p53 ubiquitination, promotes its accumulation, and activates the p53 signaling pathway [20][21][22][23][24]. ...
... Cells with MT p53, SK-BR-3, MDA-MB-231, HCC1937, and HS578T, were more sensitive to THZ1 than those without p53 mutations, MCF-7, ZR-75-1, and DU4475. Next, we determined cell viability and [23]. We hypothesized that nutlin-3 would facilitate THZ1 to repress breast cancer cell survival. ...
... Although we observed some cell inhibition after 24 h incubation, the difference between the two groups was minimal (data not shown). THZ1 obstructs gene transcriptional processes by repressing the mitotic cell cycle, and combined nutlin-3 and THZ1 treatment interfere with HCT116 cells by disrupting transcription [7,23] We hypothesized that nutlin-3 and THZ1-mediated lethality of breast cancer cells depends on extensive transcriptional interference. We verified this hypothesis by assessing the viability of MCF-7 cells treated with flavopiridol, a broad-spectrum competitive CDK inhibitor, and nutlin-3. ...
Background
The cyclin-dependent kinase 7 (CDK7) inhibitor THZ1 represses multiple cancer cells. However, its tumor-repressive efficiency in wild-type p53 breast cancer cells remains controversial.
Methods
We conducted various assays, including CCK8, colony formation, flow cytometry, western blotting, and lactate dehydrogenase release detection, to clarify whether p53 elevation sensitizes breast cancer cells to THZ1.
Results
We found that upregulating functional p53 contributes to the increased sensitivity of breast cancer cells to THZ1. Increased THZ1 sensitivity requires active p53 and an intact p53 pathway, which was confirmed by introducing exogenous wild-type p53 and the subsequent elevation of THZ1-mediated tumor suppression in breast cancer cells carrying mutant p53. We confirmed that p53 accumulates in the nucleus and mitochondria during cell death. Furthermore, we identified extensive transcriptional disruption, rather than solely CDK7 inhibition, as the mechanism underlying the nutlin-3 and THZ1-induced death of breast cancer cells. Finally, we observed the combined nutlin-3 and THZ1 treatment amplified gasdermin E cleavage.
Conclusion
Enhanced sensitivity of breast cancer cells to THZ1 can be achieved by increasing effective p53 expression. Our approach may serve as a potential treatment for patients with breast cancer resistant to regular therapies.
... CDK7, a component of the Ckd-activating kinase family, is an important target for the treatment of several cancers [49]. CDK7 is an essential component of the transcription factor TFIIH, which is involved in the transcription initiation by controlling the DNA repair and the activity of enzymes involved in the regulation of cell cycle progression (such as cyclin-dependent kinases 1, 2, 4, and 6) [50]. ...
Irinotecan (CTP-11) is one of the standard therapies for colorectal cancer (CRC). CTP-11 is enzymatically converted to the hydrophobic 7-ethyl-10-hydroxycamptothecin (SN38), a one hundred-fold more active metabolite. Conjugation of hydrophobic anticancer drugs to nanomaterials is a strategy to improve their solubility, efficacy, and selectivity. Carbon dots (CDs) have garnered interest for their small sizes (<10 nm), low toxicity, high water solubility, and bright fluorescence. This paper describes the use of CDs to improve drug vehiculation, stability, and chemotherapeutic efficiency of SN38 through a direct intracellular uptake in CRC. The covalent conjugation of SN38 to CDs via a carbamate bond provides a CD-SN38 hybrid material for slow, sustained, and pH-responsive drug release. CD-SN38 successfully penetrates the CRC cells with a release in the nucleus affecting first the cell cycle and then the cytoskeleton. Moreover, CD-SN38 leads to a deregulation of the extracellular matrix (ECM), one of the major components of the cancer niche considered a possible target therapy for reducing the cancer progression. This work shows the combined therapeutic and imaging potential of CD-based hybrid materials for the treatment of CRC. Future efforts for targeted therapy of chronic diseases characterized by altered ECM deposition, such as chronic kidney disease and chronic allograft nephropathy in kidney transplant patients are envisaged.
