Team:IIT-Madras/Description

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DESCRIPTION

Camptothecin is a topoisomerase inhibitor and is a potent anti-cancer drug used to treat ovarian cancer, colon cancer, and small cell lung cancer amongst others. India’s primary source of camptothecin is Nothapodytes nimmoniana , a plant endemic to the country’s Western Ghats. N. nimmoniana is now endangered due to overharvesting for medicinal purposes. We intend to produce camptothecin using the fungal endophyte Fusarium solani . This method will be sustainable and won't impact native biodiversity. The chassis was chosen because the camptothecin biosynthesis pathway has been elucidated, and F. solani is believed to possess most components of the pathway except for one - the enzyme strictosidine synthase (STR). Our project aims to engineer F. solani with the enzyme STR to produce camptothecin.

MOTIVATION

Camptothecin (CPT) and its analogues function by the inhibition of topoisomerase I activity in cells. It was reported that CPT activated S or G2-M arrest and the homologous recombination repair pathway in tumor cells [1]. It was demonstrated that CPT caused DNA damage by specifically targeting DNA topoisomerase I, effectively devastating a broad spectrum of tumors [2]. Two of these analogues, irinotecan and topotecan are used in cancer treatments.

There are no convenient synthetic sources for the production of CPT. We depend on the raw material from natural populations of Camptotheca acuminata and Nothapodytes nimmoniana, a plant endemic to the country’s Western Ghats, which are the only convenient sources for large scale extraction and purification of the drug.

As CPT accumulates in the stem and roots of N. nimmoniana the entire tree needs to be felled to generate biomass for the extraction of the same. N. nimmoniana, being one of India’s primary sources for camptothecin production, is now endangered due to overharvesting for medicinal purposes.

Japan, the USA and Spain which have commercialised CPT as a drug, source their dried raw material from India, which is now one of the leading exporters worldwide. The reported trade volume had exceeded 1000 tons by 2008, whereas the unreported trade is thought to be at least twice as much. The worldwide market for CPT and its analogues has currently reached 1000 million US dollars [3].

The use of the endophytic fungus allows us to synthesize CPT at an industrial scale without impacting natural biodiversity. It further allows for faster production, easier culturing, simpler downstream processing and hence an overall cheaper production process. Our project would also demonstrate that microbial systems are capable of producing plant metabolites.

REFERENCES

[1] Ikumi W, Hiroshi S, Mami Y, Kazuki S. Regeneration of transformed Ophiorrhiza pumila plants producing camptothecin. Plant Biotech 2004; 21(5):337-42

[2] Huang M, Ze-Hong M, Hong Z, Yu-Jun C, Wei Lu, Jian Ding. Chk1 and Chk2 are differentially involved in homologous recombination repair and cell cycle arrest in response to DNA double-strand breaks induced by camptothecins. Mol Cancer Ther 2008; 7(6):120-27

[3] Cuong N, Hsieh M, Huang C. Recent development in nano-sized dosage forms of plant alkaloid camptothecin-derived drugs. Recent Pat Anticancer Drug Discov 2009; 7(2):333-38.

[4] Yamazaki Y, Kitajima M, Arita M, et al. Biosynthesis of camptothecin. In silico and in vivo tracer study from [1-13C]glucose. Plant Physiol. 2004

[5]Kusari S, Zühlke S, Spiteller M. Effect of artificial reconstitution of the interaction between the plant Camptotheca acuminata and the fungal endophyte Fusarium solani on camptothecin biosynthesis. J Nat Prod. 2011