<i>BCR-Abl</i>Silencing by siRNA: A Potent Approach to Sensitize Chronic Myeloid Leukemia Cells to Tyrosine Kinase Inhibitor Therapy

Kc, Remant Bahadur; Thapa, Bindu; Ubeda, Anyeld; Jiang, Xiaoyan; Uludağ, Hasan

doi:10.1089/scd.2018.0196

Cited by 20 publications

(19 citation statements)

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“…With complexes formulated at different polymer:siRNA compositions, the performance of PEI0.6‐Chol was again significantly better at higher ratios as compared to other carriers (Figure f). Like our previous observation, growth inhibition of K562‐WT cells with TKIs treatment was dose dependent (Figure g; Kc et al, ). As expected, IC 50 values of IM was higher (~1000 n M ) than NL and DA (<200 n M ).…”

Section: Resultssupporting

confidence: 88%

“…It is essential to assess the cellular uptake of polyplexes to gain better insight into the overall efficacy of carriers (Nam et al, 2009) (Figure 6g; Kc et al, 2019). As expected, IC 50 values of IM was higher (~1000 nM) than NL and DA (<200 nM).…”

Section: Cellular Uptake Of Complexesmentioning

confidence: 63%

“…As compared with TKIs delivery, therapeutic outcomes of siRNA delivery alone in K562 cells was significantly higher and sustained (Figure ); while TKI was able to give ~60% cell death at most in our K562 cultures, BCR‐Abl siRNA treatment provided lower cell viability at times. Although synergistic activities were not explored here, we reported separately that BCR‐Abl siRNA could synergize with TKIs to generate more substantial effect especially in drug resistant CML cells, indicating siRNAs delivery as an aid to cytotoxic drugs for drug‐resistant leukemia therapy (Kc et al, ). In the line of this observation, our study showed that, the levels of cellular apoptosis after treatment with BCR‐Abl complexes was significantly increased and the effect was superior with the PEI0.6‐Chol and PEI1.2‐Chol polymer, confirming the smaller polymeric backbones to be more beneficial for inhibiting the growth of leukemia cells.…”

Section: Discussionmentioning

confidence: 97%

“…Cholesterol (Chol) derivatives of PEI2.0, PEI1.2, and PEI0.6 were prepared via N ‐acylation using cholesteryl chloroformate as described in our previous publication (Figure a; Kc, Thapa, Ubeda, Jiang, & Uludag, ). Briefly; Chol (2.22 m M ) and PEI (2.22 m M ) were separately dissolved in anhydrous chloroform and cooled on ice bath for 30 min.…”

Section: Methodsmentioning

confidence: 99%

“…In BCR-Abl-expressing cells, BCL2 (antiapoptotic protein) and BAX (proapoptotic protein) are crucial regulators in mitochondrial apoptotic pathways. Although synergistic activities were not explored here, we reported separately that BCR-Abl siRNA could synergize with TKIs to generate more substantial effect especially in drug resistant CML cells, indicating siRNAs delivery as an aid to cytotoxic drugs for drug-resistant leukemia therapy(Kc et al, 2019). As compared with TKIs delivery, therapeutic outcomes of siRNA delivery alone in K562 cells was significantly higher and sustained (Figure 6); while TKI was able to givẽ 60% cell death at most in our K562 cultures, BCR-Abl siRNA treatment provided lower cell viability at times.…”

mentioning

confidence: 94%

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Cholesterol grafted cationic lipopolymers: Potential siRNA carriers for selective chronic myeloid leukemia therapy

Remant

Thapa

Valencia-Serna

et al. 2019

J Biomedical Materials Res

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Synthetic siRNA technology has emerged as a promising approach for molecular therapy of cancer but, despite its potential for post-transcriptional gene silencing, there is an urgent need to develop efficient delivery systems particularly for difficult-totransfect, anchorage-independent cells. In this study, we designed highly hydrophobic cationic lipopolymers by grafting cholesterol (Chol) onto low-molecular weight (0.6, 1.2, and 2.0 kDa) polyethylenimines (PEIs) to enable specific siRNA therapy to chronic myeloid leukemia (CML) cells. The siRNA binding by PEI-Chol led to nanosized (100-200 nm diameter) polyplexes with enhanced ζ-potential (+20 to +35 mV) and ability to protect the loaded siRNA completely in fresh serum. The siRNA delivery to CML (K562) cells was proportional to degree of substitution and, unexpectedly, inversely proportional to molecular size of the polymeric backbone. Chol grafting with as little as~1.0 Chol/PEI on 0.6 and 1.2 kDa PEIs enabled silencing of the reporter Green Fluorescent Protein gene as well as the endogenous BCR-Abl oncogene in K562 cells. The PEI-Chol mediated delivery of siRNAs specific for BCR-Abl and KSP genes significantly arrested the growth the cells which was significantly reflected in colony formation potency of K562 cells. BCR-Able siRNA mediated therapeutic efficacy was also observed in significantly increased caspase activity and apoptosis of K562 cells. Thus, Chol-grafted low-molecular weight PEIs appear to be unique siRNA carriers to realize the molecular therapy in CML cells.

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Section: Resultssupporting

confidence: 88%

Section: Cellular Uptake Of Complexesmentioning

confidence: 63%

Section: Discussionmentioning

confidence: 97%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 94%

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Cholesterol grafted cationic lipopolymers: Potential siRNA carriers for selective chronic myeloid leukemia therapy

Remant

Thapa

Valencia-Serna

et al. 2019

J Biomedical Materials Res

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Investigation of water‐insoluble hydrophobic polyethylenimines as RNAi vehicles in chronic myeloid leukemia therapy

Ansari

Remant

Jiang

et al. 2021

J Biomedical Materials Res

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The discovery of RNA interference (RNAi) more than two decades ago opened avenues for avant‐garde cancer treatments that possess the ability to evade issues hampering current chemotherapeutic strategies, owing to its specific gene sequence‐driven mechanism of action. A potent short interfering RNA (siRNA) delivery vehicle designed to overcome physiological barriers is imperative for successful RNAi therapy. For this purpose, this study explored the characteristics and therapeutic efficacy of low‐molecular weight (MW) polyethylenimine (PEI) with high cholesterol substitution, yielding water‐insoluble polymers, in chronic myeloid leukemia (CML) K562 cells. A strong impact of cholesterol grafting on the physicochemical attributes of the resultant polymers and their corresponding complexes with siRNA was observed, with the siRNA binding capacity of polymers increasing and complex dissociation sensitivity decreasing with increase in cholesterol content of the polymers. The modified polymer complexes were significantly smaller in size and possessed higher cationic charge compared to the parent polymer. The interaction with anionic heparan sulfate preoteoglycans present on the cell surface was significant in cellular uptake of the complexes. The therapeutic efficacy of siRNA/polymer complexes was reflected in their ability to effectively silence the reporter green fluorescent protein gene and endogenous CML oncogene BCR‐ABL as well as significantly inhibit colony formation by K562 cells post BCR‐ABL silencing. The results of this study demonstrated beneficial effects of high levels of hydrophobic substitution on low MW PEI on their functional performance bestowing them the potential to be potent RNAi agents for CML therapy.

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Linoleic‐acid‐substituted polyethylenimine to silence heat shock protein 90B1 (HSP90B1) to inhibit migration of breast cancer cells

Sundaram

Uludağ

2022

The Journal of Gene Medicine

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Introduction Breast cancer continues to be one of the leading causes of death in women, and the lack of treatment options for distant metastasis warrants the need to identify and develop more effective approaches. The aim of this study was to identify and validate targets that are associated with the survival and migration of the breast cancer cells in vitro through RNA interference (RNAi) approach. Methods Linoleic‐acid‐modified polyethylenimine (PEI) polymer was used to screen a short interfering RNA (siRNA) library against numerous cell adhesion and cytoskeleton genes in MDA‐MB‐231 triple‐negative breast cell line, and the functional outcome of silencing was determined by growth and migration inhibition with further target validation studies. Results Heat shock protein 90B1 (HSP90B1) was identified as a crucial gene that is known to be involved in various breast cancer machineries, including uncontrolled proliferation and brain metastasis. The success of this approach was also due to the use of hyaluronic acid (HA) additive in lipopolymer complexes that showed a profound impact in reducing the cell viability (~50%), migration (~40%), and mRNA transcript levels (~80%) with a physiologically relevant siRNA concentration of 60 nM. The use of Dicer‐substrate siRNA proved to be beneficial in target silencing, and a combinational treatment of integrin‐β1 (ITGB1) and HSP90B1 was effective in reducing the migration of the MDA‐MB‐231 and MDA‐MB‐436 breast cancer cells. Conclusion This study demonstrates the potential to identify and silence targets using a lipid‐modified PEI/siRNA system and highlights the importance of HSP90B1 in the growth and migration of breast cancer cells.

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BCR-AblSilencing by siRNA: A Potent Approach to Sensitize Chronic Myeloid Leukemia Cells to Tyrosine Kinase Inhibitor Therapy

Cited by 20 publications

References 50 publications

Cholesterol grafted cationic lipopolymers: Potential siRNA carriers for selective chronic myeloid leukemia therapy

Cholesterol grafted cationic lipopolymers: Potential siRNA carriers for selective chronic myeloid leukemia therapy

Investigation of water‐insoluble hydrophobic polyethylenimines as RNAi vehicles in chronic myeloid leukemia therapy

Linoleic‐acid‐substituted polyethylenimine to silence heat shock protein 90B1 (HSP90B1) to inhibit migration of breast cancer cells

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