Molecular analysis of the effects of crocin on acute myeloid leukaemia, pancreatic and colon cancer

Abstract

Pancreatic and colon cancer are two of the most prevalent causes of global cancer-related deaths. While surgery and chemotherapy are standard treatment options, post-treatment outcomes often result in a poor prognosis. Likewise, one of the major impediments to the successful treatment of acute myeloid leukaemia (AML) by chemotherapeutics is the development of drug resistance. Some cancer therapies work by inhibiting the cellular messages that promote the tumour’s growth and spread. Unfortunately, given the protracted nature of cancer therapies, problems with drug resistance and toxicity can develop. Therefore, the search for viable alternatives is of urgent need that can be used to treat cancer with minimal or no toxicity.

One promising new source of anti-cancer compounds are natural products from our environment especially those that form part of our dietary supplements such as herbs and spices. This is an indication that they have been at least field tested for toxicity for a considerable length of time. Crocin which is derived from the spice saffron is one such bioactive molecule that has shown significant anticancer activity against multiple cancers. Research has indicated that its mechanism of action is by targeting signal transduction pathways that promote cancer growth and progression, invasion, angiogenesis, and metastasis.

In the first phase of this project, the molecular mechanism of crocin -induced apoptosis in pancreatic cancer was investigated. It was found that crocin significantly downregulated key anti-apoptotic proteins and upregulated key cell cycle signaling proteins in pancreatic cancer. Likewise, microarray gene-expression analysis revealed that a substantial number of genes involved in check points and cell signaling pathways were induced in the presence of crocin. This anti-cancer effect was confirmed by a reduction in tumor growth in mice and a protective effect against radiation- induced hepatic oxidative damage. Together, these results indicate that crocin has potential for the treatment and management of pancreatic cancer.

In the second phase of this study, the effect of crocin on colon cancer angiogenesis and metastasis was investigated. It was found that crocin -treated cancer cells showed significant cytotoxicity, decreased cell migration, invasion, and angiogenesis in comparison to non-cancerous cells. In addition, crocin significantly inhibited TNF-α, NF-κB and VEGF pathways in colon cancer cells. This was confirmed by an in vivo angiogenesis model. These results indicate that crocin may supresses angiogenesis and metastasis in colon cancer via TNF-α/NF-kB/VEGF pathways.

In the final phase of this study, the effect of crocin on acute myeloid leukaemia drug resistance was evaluated. In these experiments It was found that crocin reduced the resistance of daunorubicin, a standard chemotherapeutic drug for AML, by downregulating BCl-2 and Mcl-1 pathways, which are involved in resistance of majority of chemotherapeutic drugs. Besides, crocin alone or in combination with daunorubicin inhibits proliferation, migration and promote apoptosis of AML cells, which were further confirmed in in vivo studies.

In conclusion, the research presented in this thesis has advanced scientific work that focuses on cancer angiogenesis, metastasis, and drug resistance as well as crocin-mediated apoptosis activation in pancreatic, colon cancer, and AML. However, more thorough and focused analyses are still required to illuminate numerous unrecognized facets. From the studies presented so far, it is concluded that crocin has the potential to inhibit different types of cancer by modulating multiple signalling pathways and showing a minimal toxicity profile. Therefore, it is reasonable to suggest crocin as an effective and successful anticancer agent that could have patient benefits if translated into clinics.

Date of Award	Aug 2022
Original language	English
Sponsors	Vice Chanchellor's Research Scholarship & Dowager Countess Eleanor Peel Trust
Supervisor	Paul Mc Carron (Supervisor), Mateus Webba Da Silva (Supervisor) & Murtaza Tambuwala (Supervisor)