Oncology & Cancer Research

Palbociclib is a chemotherapy drug used to treat advanced breast cancers. In a phase 3 clinical trial, a combination of palbociclib and fulvestrant more than doubled median progression-free survival time in women with ER+, HER- breast cancer compared to fulvestrant alone. Palbociclib received accelerated approval from the FDA in 2015 for ER+ breast cancers, and in 2017 was approved for the treatment of HER2- breast cancers.

The cyclin-dependent kinases CDK4 and CDK6 cause cells to pass from the G1 phase to the S phase and divide. Palbociclib works by selectively inhibiting these kinases.

Recently, Miettinen et al. argued that palbociclib’s remarkable effectiveness against breast cancer can not be explained by CDK4 and CDK6 inhibition alone. They used a method called cellular thermal shift assay to investigate other targets of palbociclib within the cell. This assay measures changes in the thermal stability of proteins in living cells, which can be used to determine which proteins are bound or modified by the drug of interest.

Miettinen et al. found that palbociclib targets the proteasome in a breast cancer cell line. Palbociclib activates the proteasome by preventing the suppressor protein ECM29 from binding to it. The authors speculate that tightly regulated proteasome activity is required for cell division, so palbociclib’s activation of the proteasome could be another way that it treats breast cancer.

Miettinen TP, Peltier J, Hartlova A, Gierlinski M, Jansen VM, Trost M, Bjorklund M. Thermal proteome profiling of breast cancer cells reveals proteasomal activation by CDK4/6 inhibitor palbociclib. (2018). doi: 10.15252/embj.201798359.

Resistance to chemotherapeutics is a common adverse event in the treatment of breast cancer. The chemotherapeutic agent docetaxel is in common use as a chemotherapeutic, but resistance to treatment after long exposure is a common downfall of docetaxel. Overcoming resistance to well used chemotherapeutic agents would be a boon to the fight against cancer.

A recent article found in PLoS ONE investigates the effect of treatment of docetaxel-resistant MCF-7 breast cancer cells with microtubule destabilizing agents, in the hope of overcoming taxane-resistance. The work reported that taxane-resistant MCF-7 cells were still resistant to treatment with vinca alkaloids, but colchicine binding site agents were more potent in the docetaxel-resistant MCF-7 cells than in wild-type MCF-7 cells.

In addition to colchicine, other colchicine binding site agents also showed the same pattern against wild-type and docetaxel resistant MCF-7 cells. One such colchicine binding site agent exhibiting this property was 2-methoxyestradiol.

However, the vinka alkaloids vinorelbine and vinblastine lost potency against the docetaxel-resistant MCF-7 cells. Both of these vinka alkaloids showed about a 3-6 times decrease in potency between wild-type and taxane-resistant cells. The overall potency is still sub-micromolar in the cytotoxicity assay.

In all, colchicine binding site agents may be suitable for co-administration with docetaxel to overcome drug-resistance mechanisms.

These microtubule interacting compounds are available from LKT Laboratories, Inc. for your research needs.

V3253 Vinblastine Sulfate

V3251 Vinorelbine Base

D5709 Docetaxel

C5645 Colchicine

M1678 2-Methoxyestradiol

Wang RC, Chen X Parissenti AM, Joy AA, Tuszynski J, Brindley DN, et al. (2017) “Sensitivity of docetaxel-resistant MCF-7 breast cancer cells to microtubule-destabilizing agents including vinca alkaloids and colchicine-site binding agents.” PLoS ONE 12(8): e0182400. https://doi.org/10.1371/journal.pone.0182400

Cyclin-dependent kinases (CDKs) are an enzyme family that control cellular proliferation and growth. The interaction of CDKs with D-type cyclins results in the inactivation of retinoblastoma (Rb) tumor suppressor protein. Inhibiting the CDKs therefore allows the tumor suppressor to remain active.

Abemaciclib has previously demonstrated antitumor activity in HR+/HER2 metastatic breast cancer, renal cell carcinoma and several other solid tumor types. It’s been found to selectively inhibit CDK4 and CDK6. A recent study by Kosovec et al, further tests the potential of abemaciclib, this time for the treatment of esophageal adenocarcinoma (EAC).

The study evaluated several cell lines, monitoring apoptosis, proliferation, and pathway regulation during treatment with abemaciclib. Additionally, animals were induced to develop EAC and then treated with abemaciclib by intraperitoneal injection. The study was quite successful, the treated animals showed decreased tumor volumes and decreased prevalence of the disease altogether, while the treated cell lines showed increased apoptosis and decreased proliferation.

Overactive CDKs or inactive Rb protein are a common thread among several different cancer types, which makes CDK an interesting target of investigation for cancer treatments.

A044176 Abemaciclib

Full List of CDK Inhibitors

Reference:

Kosovec JE, Zaidi AH, Omstead NA, et al. CDK4/6 dual inhibitor abemaciclib demonstrates compelling preclinical activity against esophageal adenocarcinoma: a novel therapeutic option for a deadly disease. Oncotarget. 2017 Nov 1;8(59):100421-100432. doi: 10.18632/oncotarget.22244.

Nemorosone is a polycyclic polyprenylated acylphloroglucinol derived from beeswax and bee saliva. Closely related to hyperforin, nemorosone shows activity as an anti-cancer and anti-inflammatory compound.

Nemorosone inhibited growth of xenografts of MIA-PaCA-2 pancreatic cancer cells in mice over a 28-day trial period. Nemorosone showed better activity than standard treatment with gemcitabine in the same model. Additionally, nemorosone does not activate CYP3A4, unlike structurally related molecule hyperforin. Nemorosone, therefore, has a longer half-life and better absorption in biological systems.

Nemorosone is available exclusively from LKT Laboratories, Inc.

N176498 Nemorosone

H9863 Hyperforin Dicyclohexylammonium

G1745 Gemcitabine Hydrochloride

Reference:

Wolf, RJ, Hilger RA, Hoheisel JD, et al. (2013) “In Vivo Activity and Pharmacokinetics of Nemorosone on Pancreatic Cancer Xenografts.” PLoS ONE 8(9): e74555. Doi:10.1371/journal.pone.0074555

PAC-1 (Procaspase activating compound 1) is an anti-cancer compound that works against a multitude of cancer types. PAC-1 works by binding zinc ions that inactivate the activity of procaspase-3.

Procaspase-3 is the zymogen form of caspase-3. High expression of procaspase-3 is found in a variety of cancer types including brain, breast, lung and colon cancers. Because of its high expression in some rare carcinoma, procaspase-3 is an excellent anti-cancer target. Caspase-3 is needed for cells to undergo apoptosis, or programmed cell-death. Procaspase-3 is activated to caspase-3 by caspase-8 or caspase-9, after the apoptosis signaling cascade is begun.

One atom that inhibits the activation of procaspase-3 to caspase-3 is endogenous zinc found in cells. PAC-1 selectively chelates to zinc ions bound to procaspase-3. With PAC-1 chelating to zinc ions, pro-caspase-3 is activated to caspase-3 and cancerous cells can undergo apoptosis. PAC-1 has recently been used in a phase I clinical trial for efficacy against glioblastoma. PAC-1 is an attractive molecule against this cancer type due to its ability to cross the blood-brain barrier in the body.

PAC-1 also acts synergistically with some common cancer treatments. It has been shown that PAC-1 can act synergistically with doxorubicin, both in vitro and in vivo. Experiments in canines showed that both canine lymphoma and canine osteosarcoma tumors regressed with combined doxorubicin/PAC-1 treatment.

PAC-1 is available now from LKT Laboratories, Inc.

P004080 PAC-1

References:

1. Putt, K.S., Chen, G.W., Pearson, J. M. et al. “Small-molecule activation of procaspase-3 to caspase-3 as a personalized anticancer strategy.” Nature Chem. Biol. 2006 Oct; 2(10): 543-550. Doi:10.1038/nchembio814.

2. Botham, R. C., Roth, H. S., Book, A.P. et al. “Small-Molecule Procaspase-3 Activation Sensitizes Cancer to Treatment with Diverse Chemotherapeutics.” ACS Cent. Sci. 2016 Aug 24; 2(8):545-59. Doi: 10.1021/acscentsci.6b00165.

The NOTCH signaling pathway is involved in cell proliferation, differentiation and cell cycle progression. Four membrane-bound NOTCH receptors are found in mammals (NOTCH1, NOTCH2, NOTCH3 and NOTCH4), which interact with 5 different extracellular ligands (Jagged 1, jagged 2, delta like ligand 1, 3 and 4). Ligands bind NOTCH on the extracellular domain, starting the NOTCH signaling cascade, eventually resulting in release of the NOTCH intracellular domain (NICD). The NICD then translocates to the nucleus, effecting the activation of various genes, such as hairy/enhancer of split (HES).

γ-secretase is responsible for cleavage of the NOTCH intracellular domain from the transmembrane portion of the protein. Inhibitors of γ-secretase (GSIs) therefore are useful as inhibitors of the NOTCH signaling cascade. NOTCH signaling inhibitors have been extensively studied in hematological malignancies, as well as other cancerous tissues. LKT Laboratories offers a variety of γ-secretase inhibitors.

MK-0752 (3-[4-(4-chlorophenyl) sulfonyl-4-(2,5-difluorophenyl) cyclohexyl] propanoic acid) was also submitted for phase I clinical trials. Results of this test show that MK-0752 was tolerated by patients with advanced solid tumors, and showed efficacy as an anti-cancer agent.

DAPT (N-[N-(3,5- Difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester) was found to inhibit the proliferation of ovarian cancer cells, as well as inducing apoptosis of these cells. DAPT also inhibits proliferation of gastric carcinmoma cells.

These γ-secretase inhibitors and more are available from LKT Labs Inc.

F4432 FLI-06

D0260 DAPT

D1773 Deshydroxy LY-411575

M4200 MK-0752

References:

Yuan X., Wu H., et al. “Notch signaling: An emerging therapeutic target for cancer treatment” Cancer Letters 369, (2015) pp 20-27. Doi: 10.1016/j.canlet.2015.07.048

Yao, Y., Ni, Y. et al. “The role of Notch signaling in gastric carcinoma: molecular pathogenisis and novel therapeutic targets.” Oncotarget. (2017) May 11. Doi: 10.18632/oncotarget.17809.

Feng, Z., Xu, W. et al. “Inhibition of gamma-secretase in Notch1 signaling pathway as a novel treatment for ovarian cancer.” Oncotarget. (2017) Jan 31; 8(5):8283-8293. Doi:10.18632/oncotarget.14152.

Gu, Y., Masiero, M. and Banham AH. “Notch signaling: its roles and therapeutic potential in hematological malignancies.” Oncotarget. (2016) May 17;7(20):29804-23. Doi: 10.18632/oncotarget.7772.

MYC is a frequently deregulated oncogene in many human cancers. It is normally responsible for facilitating cell growth and proliferation through the encoding of transcription factors. Since many types of cancers are dependent on the upregulation of MYC, reducing MYC protein levels by targeting its upstream regulators such as histone deacetylases (HDAC) and phophoinositide 3-kinases (PI3K) may be a viable and effective method of treatment.

CUDC-907 is an inhibitor of PI3K and class I and II HDACs. In a recent study published in Molecular Cancer Therapeutics, it was shown that PI3K and HDAC inhibition synergistically downregulated MYC protein levels and induced apoptosis in “double-hit” (DH) diffuse large B-cell lymphoma (DLBCL) cells. CUDC-907 suppressed the growth and survival of MYC-altered or MYC-dependent cancer cells through this downregulation of the MYC protein. Further research and development utilizing CUDC-907 in MYC-driven cancers may be pursued thanks to this study.

LKT Laboratories carries CUDC-907 as well as a number of other PI3K inhibitors for research use.

C8112 CUDC-907

PI3K inhibitor list

Kaiming S., Ruzanna A., et al. Dual HDAC and PI3K inhibitor CUDC-907 Downregulates MYC and Suppresses Growth of MYC-dependent Cancers. Mol Cancer Ther 2016.

Cabozantinib is a chemotherapeutic compound that has shown potential as a treatment for medullary thyroid cancer and other types of solid tumors. It is primarily known for its inhibition of c-Met and vascular endothelial growth factor receptor 2 (VEGFR-2). By inhibiting these tyrosine kinases Cabozantinib reduces tumor growth, metastasis, and angiogenesis.

In a 2016 study, cabozantinib showed activity against gastrointestinal stromal tumors (GIST). In many cases of GIST, oncogenic signaling is driven by KIT mutations. Tyrosine kinase inhibitors (TKI) such as imatinib have been used to treat GIST, but resistance to TKI caused by secondary mutations to KIT sometimes renders this treatment ineffective.

Cabozantinib was tested in patient-derived xenograft models of GIST, with each model carrying different KIT mutations. Three different models were examined in total, and in all three cabozantinib inhibited proliferative activity, even in those models that were imatinib-resistant. Compared to an imatinib treated group and a control group, cabozantinib also significantly reduced microvessel density in all three models.

From the study it was concluded that cabozantinib shows promising antitumor activity in both imatinib-sensitive and imatinib-resistant GIST models. The activity is achieved through the inhibition of tumor growth, proliferation, and angiogenesis, and may provide a valid alternate treatment method for GIST going forward.

C0006 Cabozantinib

I4802 Imatinib Mesylate

Gebreyohannes Y., Schoffski P., et al. Cabozantinib is Active against Human Gastrointestinal Stromal Tumor Xenografts Carrying Different KIT Mutations. Mol Cancer Ther; 15(12); 2845-52.

Piperlongumine is found in several species of the Piper plant and displays many beneficial characteristics, including antithrombotic, anti-inflammatory, anti-atherosclerotic, and chemotherapeutic activities. Isolated from the fruit of the long pepper, recent research has focused on the ability of this natural product to suppress tumor growth alone and in combination with other chemotherapeutic compounds.

In a study published in 2015, the effects of Piperlongumine were examined in pancreatic cancer cells. Pancreatic cancer is an aggressive malignancy with a relatively poor prognosis, even in cases where it is diagnosed early. There are few good options for chemotherapy.

In vitro, piperlongumine showed inhibition of pancreatic cancer cell lines, inhibited the activation of NF-kB, and also potentiated the apoptotic effects of gemcitabine, a nucleoside analog commonly used in the chemotherapeutic treatment of some cancers. Piperlongumine went on to show significant activity in vivo, where it suppressed tumor growth alone and enhanced the efficacy of gemcitabine in xenograft mouse models. These results were consistent with the downregulation of NF-kB activity and its target genes, decreased proliferation, and increased apoptosis in tumor remnants seen in the model.

The results of the study suggest both potential for piperlongumine as a stand-alone treatment for human pancreatic cancer, as well as a partner-chemotherapeutic with compounds like gemcitabine. Both piperlongumine and gemcitabine are available from LKT Labs for research use.

P3561 Piperlongumine

G1745 Gemcitabine Hydrochloride

Wang Y., Wu X., et al. Piperlongumine Suppresses Growth and Sensitizes Pancreatic Tumors to Gemcitabine in a Xenograft Mouse Model by Modulating the NF-kappa B Pathway. Cancer Prev. Res. Mar;9(3):234-44.

Barasertib, also known as AZD-1152, is a highly selective aurora kinase B inhibitor. As an aurora kinase inhibitor, it has shown the ability to disrupt the cell cycle and consequently induce apoptosis in vitro. It has inhibited the growth of human colon, lung, and haematologic tumor xenografts in immunodeficient mice, and continues to be evaluated in various disease models.

In a 2016 study, barasertib inhibited the growth of small-cell lung cancer cells in vitro and in vivo. Small-cell lung cancer cells are good targets for aurora kinase inhibition, thanks to their rapid proliferation and high rates of MYC family amplification. Inhibitors of mitosis such as aurora kinase inhibitors have been effective in causing apoptosis in cells expressing high levels of MYC in other tumor types.

A panel of small-cell lung cancer lines with and without MYC family gene amplification was screened for growth inhibition by barasertib. The growth inhibition caused by barasertib correlated with cMYC amplification and cMYC gene expression in the panel. Small-cell lung cancer tumors with high cMYC amplification or gene expression may thus be good targets for barasertib and other aurora kinase B inhibitors.

LKT Labs sells a number of aurora kinase inhibitors, including AZD1152:

A9714 AZD-1152-HQPA

M4652 MLN-8237

T5996 Tozasertib

Z4900 ZM-447439 Trihydrate

References:

Helfrich B., Kim J., et al. Barasertib (AZD1152), a Small Molecule Aurora B Inhibitor, Inhibits the Growth of SCLS Cell Lines In Vitro and In Vivo. Mol Cancer Ther; 15(10); 2314-22. PMID: 27496133.