An mTORC1/2 kinase inhibitor enhances the cytotoxicity of gemtuzumab ozogamicin by activation of lysosomal function

Maimaitili, Yimamu; Inase, Aki; Miyata, Yoshiharu; Kitao, Akihito; Mizutani, Yu; Kakiuchi, Seiji; Shimono, Yohei; Saito, Yasuyuki; Sawada, Takashi; Minami, Hironobu; Matsuoka, Hiroshi

doi:10.1016/j.leukres.2018.09.017

Cited by 14 publications

(19 citation statements)

References 37 publications

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“…In agreement with this, GO treatment was found to induce p38 stress kinase activation and to cause the cell death mediators, Bak and Bax, to adopt a pro-apoptotic conformation in two sensitive AML cell lines but not in a resistant one [18]. Maimaitili et al found that in six of eight tested AML cell lines, the cytotoxicity of GO could be synergistically enhanced by concurrent treatment with the mTORC1/2 inhibitor, PP242 [19]. GO sensitization of cells by PP242 is mediated by a dual mechanism that combines enhanced lysosomal function with blockage of activation of the checkpoint kinase Chk1, a key regulator of DNA damage-induced cell cycle arrest.…”

Section: Fda-approved Adcsmentioning

confidence: 79%

Acquired Resistance to Antibody-Drug Conjugates

Collins

Bossenmaier²,

Kollmorgen

et al. 2019

Cancers

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Antibody-drug conjugates (ADCs) combine the tumor selectivity of antibodies with the potency of cytotoxic small molecules thereby constituting antibody-mediated chemotherapy. As this inherently limits the adverse effects of the chemotherapeutic, such approaches are heavily pursued by pharma and biotech companies and have resulted in four FDA (Food and Drug Administration)-approved ADCs. However, as with other cancer therapies, durable responses are limited by the fact that under cell stress exerted by these drugs, tumors can acquire mechanisms of escape. Resistance can develop against the antibody component of ADCs by down-regulation/mutation of the targeted cell surface antigen or against payload toxicity by up-regulation of drug efflux transporters. Unique resistance mechanisms specific for the mode of action of ADCs have also emerged, like altered internalization or cell surface recycling of the targeted tumor antigen, changes in the intracellular routing or processing of ADCs, and impaired release of the toxic payload into the cytosol. These evasive changes are tailored to the specific nature and interplay of the three ADC constituents: the antibody, the linker, and the payload. Hence, they do not necessarily endow broad resistance to ADC therapy. This review summarizes preclinical and clinical findings that shed light on the mechanisms of acquired resistance to ADC therapies.

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Section: Fda-approved Adcsmentioning

confidence: 79%

Acquired Resistance to Antibody-Drug Conjugates

Collins

Bossenmaier²,

Kollmorgen

et al. 2019

Cancers

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“…Results of the enzymatic activity assay also illustrated that cathepsin L activity was significantly decreased upon NJXA treatment, but increased by positive control drugs ( Figure 4 E). PP242 (Torkinib) and torin-1 were used as positive drugs as they are known activators of lysosomal activity [ 18 ]. LysoTracker Red staining revealed that NJXA significantly blocked the fluorescence of LysoTracker Red ( Figure 4 F), while PP242 strengthened it, indicating that NJXA downregulated lysosomal activity.…”

Section: Resultsmentioning

confidence: 99%

Nujiangexanthone A Inhibits Cervical Cancer Cell Proliferation by Promoting Mitophagy

Feng

Mansouripour

et al. 2021

Molecules

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Nujiangexanthone A (NJXA), a bioactive component isolated from the leaves of Garcinia nujiangensis, has been reported to exhibit anti-inflammatory, antioxidant, and antitumor effects. Our previous work has shown that NJXA induced G0/1 arrest and apoptosis, thus suppressing cervical cancer cell growth. The present study provides new evidence that NJXA can induce cell death in HeLa cells by promoting mitophagy. We first identified that NJXA triggered GFP-LC3 and YFP-Parkin puncta accumulation, which are biomarkers of mitophagy. Moreover, NJXA degraded the mitochondrial membrane proteins Tom20 and Tim23 and mitochondrial fusion proteins MFN1 and MFN2, downregulated Parkin, and stabilized PINK1. Additionally, we revealed that NJXA induced lysosome degradation and colocalization of mitochondria and autophagosomes, which was attenuated by knocking down ATG7, the key regulator of mitophagy. Furthermore, since mitophagy is induced under starvation conditions, we detected the cytotoxic effect of NJXA in nutrient-deprived HeLa cells and observed better cytotoxicity. Taken together, our work contributes to the further clarification of the mechanism by which NJXA inhibits cervical cancer cell proliferation and provides evidence that NJXA has the potential to develop anticancer drugs.

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“…SKM‐1 is a cell line derived from a patient with MDS/AML, which has no chromosomal abnormalities but has point mutations in NRAS and KRAS 20 . We also used the MDS/AML cell lines, TF‐1, 21 MOLM‐13, 22 and SKK‐1, 23 and AML cell lines, HL‐60 and THP‐1. PTC‐028 induced the dose‐dependent inhibition of cell proliferation on both MDS and AML cells (Figure 2A).…”

Section: Resultsmentioning

confidence: 99%

Efficacy of the novel tubulin polymerization inhibitor PTC‐028 for myelodysplastic syndrome

et al. 2020

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Monomer tubulin polymerize into microtubules, which are highly dynamic and play a critical role in mitosis. Therefore, microtubule dynamics are an important target for anticancer drugs. The inhibition of tubulin polymerization or depolymerization was previously targeted and exhibited efficacy against solid tumors. The novel small molecule PTC596 directly binds tubulin, inhibits microtubule polymerization, downregulates MCL‐1, and induces p53‐independent apoptosis in acute myeloid leukemia cells. We herein investigated the efficacy of PTC‐028, a structural analog of PTC596, for myelodysplastic syndrome (MDS). PTC‐028 suppressed growth and induced apoptosis in MDS cell lines. The efficacy of PTC028 in primary MDS samples was confirmed using cell proliferation assays. PTC‐028 synergized with hypomethylating agents, such as decitabine and azacitidine, to inhibit growth and induce apoptosis in MDS cells. Mechanistically, a treatment with PTC‐028 induced G2/M arrest followed by apoptotic cell death. We also assessed the efficacy of PTC‐028 in a xenograft mouse model of MDS using the MDS cell line, MDS‐L, and the AkaBLI bioluminescence imaging system, which is composed of AkaLumine‐HCl and Akaluc. PTC‐028 prolonged the survival of mice in xenograft models. The present results suggest a chemotherapeutic strategy for MDS through the disruption of microtubule dynamics in combination with DNA hypomethylating agents.

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An mTORC1/2 kinase inhibitor enhances the cytotoxicity of gemtuzumab ozogamicin by activation of lysosomal function

Cited by 14 publications

References 37 publications

Acquired Resistance to Antibody-Drug Conjugates

Acquired Resistance to Antibody-Drug Conjugates

Nujiangexanthone A Inhibits Cervical Cancer Cell Proliferation by Promoting Mitophagy

Efficacy of the novel tubulin polymerization inhibitor PTC‐028 for myelodysplastic syndrome

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