HSP90 inhibitors under development for pancreatic cancer therapy

Celastrol is a triterpenoid compound (figure 1) which can be produced from the leaves of a plant used in traditional Chinese medicine called Tripterygium wilfordii  or 雷公藤 [1]. Celastrol prevents interaction between HSP90 and its cochaperone CDC37. It has no effect on ATP binding to HSP90 which most other inhibitors target [2].

celastrol
Figure 1: Celastrol. Credit: Ed (Edgar181). No changes were made. Creative Commons Public Domain Mark 1.0.

HSP90s are a family of chaperone proteins that function to stabilise, regulate and activate a range of so called client proteins [3]. The particular subset of client proteins they interact with is determined by the cochaperone. CDC37 facilitates the interaction of HSP90 with a number of kinases with important functions in cancer such as SRC, RAF1 and AKT [4].

Treatment of the cancer cell line Panc-1 with Celastrol induced apoptosis, reduced the tumour volume of Panc-1 mouse xenografts and increased the survival time of mice bearing those xenografts [2]. Clinical trials using other single agent HSP90 inhibitors for pancreatic cancer have not been successful to date [5,6]. However combination strategies that target chemotherapeutic agents via conjugation to HSP90 inhibitors and HSP90 inhibitor incorporation into nanoparticles are under development which may be more effective [7,8].

Refs

  1. William T. Chalmers James P. Kutney Phillip J. Salisbury Kenneth L. Stuart Phillip M. Townsley Brian R. Worth (1982). Method for producing tripdiolide, triptolide and celastrol, US patent US4328309A. 1982-05-04.
  2. Zhang T, Hamza A, Cao X, Wang B, Yu S, Zhan CG, Sun D. A novel Hsp90 inhibitor to disrupt Hsp90/Cdc37 complex against pancreatic cancer cells. Mol Cancer Ther. 2008 Jan;7(1):162-70. doi: 10.1158/1535-7163.MCT-07-0484. PubMed PMID: 18202019.
  3. Pearl LH. Review: The HSP90 molecular chaperone-an enigmatic ATPase. Biopolymers. 2016 Aug;105(8):594-607. doi: 10.1002/bip.22835. Review. PubMed PMID: 26991466.
  4. Pearl LH. Hsp90 and Cdc37 — a chaperone cancer conspiracy. Curr Opin Genet Dev. 2005 Feb;15(1):55-61. Review. PubMed PMID: 15661534.
  5. PhII Study STA-9090 as Second or Third-Line Therapy for Metastatic Pancreas Cancer. ClinicalTrials.gov Identifier NCT01227018
  6. Study of AUY922 in Metastatic Pancreatic Cancer Who Are Resistant to First Line Chemotherapy. ClinicalTrials.gov Identifier: NCT01484860
  7. Bobrov E, Skobeleva N, Restifo D, Beglyarova N, Cai KQ, Handorf E, Campbell K, Proia DA, Khazak V, Golemis EA, Astsaturov I. Targeted delivery of chemotherapy using HSP90 inhibitor drug conjugates is highly active against pancreatic cancer models. Oncotarget. 2016 Oct 13. doi: 10.18632/oncotarget.12642. PubMed PMID: 27779106.
  8. Rochani AK, Balasubramanian S, Ravindran Girija A, Raveendran S, Borah A, Nagaoka Y, Nakajima Y, Maekawa T, Kumar DS. Dual mode of cancer cell destruction for pancreatic cancer therapy using Hsp90 inhibitor loaded polymeric nano magnetic formulation. Int J Pharm. 2016 Sep 10;511(1):648-58. Doi: 10.1016/j.ijpharm.2016.07.048. PubMed PMID: 27469073.
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Targeting amino acid metabolism as a therapeutic strategy for pancreatic cancer

 

Amino acid metabolism plays an important role in pancreatic cancer. Targeting of amino acid metabolism in both the tumour and the microenvironment can trigger cancer cell death and relieve immunosuppression which is important for effective immunotherapy.

 

The activity of the enzyme Indoleamine-pyrrole 2,3-dioxygenase (IDO1) in tumours leads to suppression of the immune system [1]. IDO1 catalyzes the degradation of the amino acid L-tryptophan to N-formylkynurenine which impairs CD4+ T cell receptor activation and leads to CD8+ T cell suppression/anergy. Furthermore the activity of IDO1 in tumour cells and TAMs leads to the depletion of L-tryptophan in the microenvironment which in turn triggers a stress response in dendritic cells leading to their deactivation [2]. The activity of dendritic cells is crucial to an immune response against cancer. IDO1 inhibitors are in clinical development (see here).

 

Arginine depletion via the enzyme arginase 1 (ARG1) by tumour associated macrophages (TAMs) and myeloid derived suppressor cells (MDSCs) inhibits the activity of CD4+ T cells in the tumour microenvironment. ARG1 and 2 inhibitors have been developed for treatment of myocardial reperfusion injury [3], however they could also be applied to pancreatic cancer. These compounds are available from the authors upon request [3].

 

By analysing the publically available pancreatic cancer microarray datasets available in the GEO database the authors of a recent paper identified the amino acid transporter SLC6A14 as consistently upregulated in pancreatic cancer [4]. Using LC3 as a marker of autophagy the authors demonstrated that pharmacologic inhibition of SLC6A14 induced autophagy in BxPC3 pancreatic cancer cells. Furthermore pharmacologic inhibition of SLC6A14 significantly reduced tumour volumes in pancreatic cancer mouse xenograft models. It should be noted that, although significant, shRNA mediated ablation of SLC6A14 was not as effective in the xenograft models which could indicate that the pharmacologic inhibition is broader than expected assuming shRNA ablation of SLC6A14 in mouse xenograft is stable [4].

 

Thus targeting amino acid metabolism in pancreatic cancer can potentially induce cancer cell death and relieve immunosuppression, important aspects for the successful completion of the cancer immunity cycle [5].

 

Refs

 

  1. Adams JL, Smothers J, Srinivasan R, Hoos A. Big opportunities for small molecules in immuno-oncology. Nat Rev Drug Discov. 2015 Sep;14(9):603-22. doi: 10.1038/nrd4596. Epub 2015 Jul 31. Review. PubMed PMID: 26228631.
  2. Soliman H, Mediavilla-Varela M, Antonia S. Indoleamine 2,3-dioxygenase: is it an immune suppressor? Cancer J. 2010 Jul-Aug;16(4):354-9. Doi:10.1097/PPO.0b013e3181eb3343. Review. PubMed PMID: 20693847.
  3. Van Zandt MC, Whitehouse DL, Golebiowski A, Ji MK, Zhang M, Beckett RP, Jagdmann GE, Ryder TR, Sheeler R, Andreoli M, Conway B, Mahboubi K, D’Angelo G, Mitschler A, Cousido-Siah A, Ruiz FX, Howard EI, Podjarny AD, Schroeter H. Discovery of (R)-2-amino-6-borono-2-(2-(piperidin-1-yl)ethyl)hexanoic acid and congeners as highly potent inhibitors of human arginases I and II for treatment of myocardial reperfusion injury. J Med Chem. 2013 Mar 28;56(6):2568-80. Doi: 10.1021/jm400014c. PubMed PMID: 23472952.
  4. Coothankandaswamy V, Cao S, Xu Y, Prasad PD, Singh PK, Reynolds CP, Yang S, Ogura J, Ganapathy V, Bhutia YD. Amino acid transporter SLC6A14 is a novel and effective drug target for pancreatic cancer. Br J Pharmacol. 2016 Oct 17. Doi: 10.1111/bph.13616. PubMed PMID: 27747870.
  5. Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity. 2013 Jul 25;39(1):1-10. doi: 10.1016/j.immuni.2013.07.012. Review. PubMed PMID: 23890059.

Phycocyanin extract from blue-green algae (cyanobacteria) induced autophagic cell death in pancreatic cancer cell lines

Phycocyanin is a pigment-protein complex produced by certain cyanobacteria. It is composed of two protein subunits α-phycocyanin (18.4 kDa) and β-phycocyanin (21.3 kDa). As its name suggests phycocyanin in solution produces a blue-green colour (figure 1). Stable isolation of phycocyanin from Spirulina platensis has been achieved with a high pressure extraction process [1].

 

extracted_phycocyanin
Figure 1: Phycocyanin pigment extracted from Microcystis aeruginosa. The pigments light blue colour is evident. Credit: CyanoLakes. No changes were made. Creative Commons Attribution-Share Alike 4.0 International (CC-BY-SA-4.0).

 

Using phycocyanin extracted from this source a recent study demonstrated that it induced cell death in pancreatic cancer cell lines through a mechanism involving autophagy [2]. Interestingly on a panel of non-tumour cell lines phycocyanin had little effect. When beclin-1 was ablated by siRNA, which normally blocks autophagy, cell viability was rescued in phycocyanin treated pancreatic cancer cells [2].

 

In other models phycocyanin raised reactive oxygen species levels associated with apoptosis [3]. KRAS mutant cancers such as pancreatic are known to be sensitive to redox shifts so it is of interest as to whether phycocyanin has a direct effect on the redox balance of pancreatic cancer cells.  

 

Refs

 

  1. Seo YC, Choi WS, Park JH, Park JO, Jung KH, Lee HY. Stable isolation of phycocyanin from Spirulina platensis associated with high-pressure extraction process. Int J Mol Sci. 2013 Jan 16;14(1):1778-87. doi: 10.3390/ijms14011778. PubMed PMID: 23325046.
  2. Liao G, Gao B, Gao Y, Yang X, Cheng X, Ou Y. Phycocyanin Inhibits Tumorigenic Potential of Pancreatic Cancer Cells: Role of Apoptosis and Autophagy. Sci Rep. 2016 Oct 3;6:34564. doi: 10.1038/srep34564. PubMed PMID: 27694919.
  3. Pardhasaradhi BV, Ali AM, Kumari AL, Reddanna P, Khar A. Phycocyanin-mediated apoptosis in AK-5 tumor cells involves down-regulation of Bcl-2 and generation of ROS. Mol Cancer Ther. 2003 Nov;2(11):1165-70. PubMed PMID: 14617790.

Chinese medicine flower, San Qi Hua, extract RN1 inhibited pancreatic cancer cell growth by targeting galectin-3

An arabinogalactan polysaccharide known as RN1 can be extracted from the flower (San Qi Hua) of the chinese medicine herb Panax notoginseng [1]. In Latin, the word panax means “cure-all”. According to Chinese medicine (Figure 1) it is warm in nature, with a sweet but slightly bitter taste. A concoction incorporating Panax notoginseng was carried by the Viet Cong to deal with wounds during the Vietnam war.

 

4832741438_6406572fe9_z
Figure 1: Yu Garden and Bazaar – Located in the heart of Old Town Shanghai, it includes a 5-acre classical Chinese garden, and the City God Daoist Temple. Credit: Lyn Gateley. No changes were made. Creative Commons Attribution 2.0 Generic (CC BY 2.0).

 

RN1 is a 20.5 kDa arabinogalactan polysaccharide. A recent study found that it inhibited the growth of two commonly used pancreatic cancer cell lines but not cell lines originating from other cancers (A549, MDA-MB-231, A172, HeLa) [2]. It also did not affect the immortalised pancreatic duct epithelial cell line HPDE6-C7. This suggests a possible synthetic lethality specific for pancreatic cancer. In addition RN1 reduced the tumour volume of both BxPC-3 cell line and pancreatic cancer patient derived mouse xenografts.

 

Galectin-3 (Gal-3) is upregulated in pancreatic cancer (see here). The authors found that RN1 bound to Gal-3 and down-regulated its protein expression in pancreatic cancer cell lines. Gal-3 induces the EGFR, BMPR, and Integrin signalling pathways and the authors provided evidence that RN1 modulated the activity of all three of these pathways in pancreatic cancer cell lines. Interestingly RN1 inhibited Runx2 expression which is known to mediate gemcitabine resistance in pancreatic cancer cell lines (see here). The targeting of Gal-3 is an interesting strategy for pancreatic cancer therapeutic development.   

 

Refs

 

  1. 丁侃, 王培培, 张蕾 (2015). Arabinogalactan of flowers of panax notoginseng (burK.)F.H.Chen, and preparation method and use thereof. Chinese patent CN 104710538 A. Jun 17, 2015.
  2. Zhang L, Wang P, Qin Y, Cong Q, Shao C, Du Z, Ni X, Li P, Ding K. RN1, a novel galectin-3 inhibitor, inhibits pancreatic cancer cell growth in vitro and in vivo via blocking galectin-3 associated signaling pathways. Oncogene. 2016 Sep 12. Doi: 10.1038/onc.2016.306. PubMed PMID: 27617577.