Related Experiment Video
Updated: Jun 5, 2026
In Vivo Inhibition of MicroRNA to Decrease Tumor Growth in Mice
Published on: August 23, 2019
Antisense inhibition of survivin expression as a cancer therapeutic
Rosa A Carrasco1, Nancy B Stamm, Eric Marcusson
1Division of Cancer Research, Lilly Research Laboratory, Indianapolis, Indiana 46285-0424, USA.
Abstract:
Survivin, a family member of the inhibitor of apoptosis proteins that is expressed during mitosis in a cell cycle-dependent manner and localized to different components of the mitotic apparatus, plays an important role in both cell division and inhibition of apoptosis. Survivin is expressed in a vast majority of human cancers, but not in normal adult tissues. Survivin expression is often correlated with poor prognosis in a wide variety of cancer patients. These features make survivin an attractive target against which cancer therapeutics could be developed. We have identified a survivin antisense oligonucleotide (ASO) that potently downregulated survivin expression in human cancer cells derived from lung, colon, pancreas, liver, breast, prostate, ovary, cervix, skin, and brain as measured by quantitative RT-PCR and immunoblotting analysis. Specific inhibition of survivin expression in multiple cancer cell lines by this ASO (LY2181308) induced caspase-3-dependent apoptosis, cell cycle arrest in the G(2)-M phase, and multinucleated cells. We also showed that inhibition of survivin expression by LY2181308 sensitized tumor cells to chemotherapeutic-induced apoptosis. Most importantly, in an in vivo human xenograft tumor model, LY2181308 produced significant antitumor activity as compared with saline or its sequence-specific control oligonucleotide and sensitized to gemcitabine, paclitaxel, and docetaxel. Furthermore, we showed that this antitumor activity was associated with significant inhibition of survivin expression in these xenograft tumors. On the basis of these, LY2181308 is being evaluated in a clinical setting (Phase II) in combination with docetaxel for the treatment of prostate cancer.
Insights
A novel survivin antisense oligonucleotide (ASO), LY2181308, effectively reduces survivin expression in diverse human cancers. This inhibition triggers cancer cell death and enhances chemotherapy effectiveness, showing promise for cancer treatment.
Area of Science:
- Oncology
- Molecular Biology
- Drug Development
Background:
- Survivin is a key protein in cell division and apoptosis inhibition, overexpressed in most human cancers but not normal tissues.
- High survivin expression correlates with poor prognosis, making it a significant therapeutic target.
- Targeting survivin offers a potential strategy for novel cancer therapeutics.
Purpose of the Study:
- To evaluate the efficacy of a survivin antisense oligonucleotide (ASO), LY2181308, in downregulating survivin expression.
- To assess the impact of LY2181308 on cancer cell apoptosis, cell cycle, and chemosensitivity.
- To investigate the in vivo antitumor activity of LY2181308 in a xenograft model and its combination effects with chemotherapy.
Main Methods:
- Quantitative RT-PCR and immunoblotting were used to measure survivin downregulation in various human cancer cell lines.
- Cancer cell lines were treated with LY2181308 to assess apoptosis, cell cycle arrest (G2-M phase), and multinucleation.
- In vivo studies utilized human xenograft tumor models treated with LY2181308, alone and in combination with chemotherapeutics (gemcitabine, paclitaxel, docetaxel).
Main Results:
- LY2181308 potently inhibited survivin expression across lung, colon, pancreatic, liver, breast, prostate, ovarian, cervical, skin, and brain cancer cell lines.
- Survivin inhibition by LY2181308 induced caspase-3-dependent apoptosis, G2-M cell cycle arrest, and multinucleated cells.
- LY2181308 demonstrated significant antitumor activity in vivo and sensitized tumors to chemotherapy, with activity linked to survivin inhibition.
Conclusions:
- The survivin ASO LY2181308 effectively targets survivin in multiple cancer types, inducing cell death and enhancing chemotherapy efficacy.
- LY2181308 exhibits promising antitumor activity in preclinical models, warranting clinical investigation.
- LY2181308 is currently under Phase II clinical evaluation for prostate cancer treatment in combination with docetaxel.
Related Concept Videos
02:30siRNA - Small Interfering RNAs
In the cytoplasm, siRNA is processed from a double-stranded RNA, which comes from either endogenous DNA transcription or exogenous sources like a virus. This double-stranded RNA is then cleaved by the ATP-dependent...
02:57Targeted Cancer Therapies
There are several types of targeted therapies against specific...
02:57Targeted Cancer Therapies
There are several types of targeted therapies against specific...
01:12Loss of Tumor Suppressor Gene Functions
When the tumor suppressor genes develop mutations or are lost, cells start growing out of control, leading to cancer. However, a single functional copy of the tumor suppressor gene is enough for the cells to maintain their normal functions and cell...
01:12Loss of Tumor Suppressor Gene Functions
When the tumor suppressor genes develop mutations or are lost, cells start growing out of control, leading to cancer. However, a single functional copy of the tumor suppressor gene is enough for the cells to maintain their normal functions and cell...
03:03mTOR Signaling and Cancer Progression
The mTOR pathway or the...