Natural Marine Anticancer compounds and their derivatives used in Clinical Trials

Arijita Singla¹, Varsha Singh¹, Komal Kumari¹, Sonam Pathak¹, Arjun Singh²*

¹Department of Pharmacology, School of Pharmaceutical Sciences, Bhagwant University, Sikar Road,

Ajmer, Rajasthan 305004, India.

²Department of Medicine, Sidney Kimmel Medical College, Thomas Jefferson University,

Philadelphia, PA 19107, United States.

*Corresponding Author E-mail: arjunphar@gmail.com

ABSTRACT:

Cancer remains a global challenge for clinicians and researchers alike, with an increasing mortality rate. Despite enormous progress in anticancer drug discovery, there is a constant demand for novel therapeutic agents due to resistance to existing chemotherapeutic drugs and their adverse side effects. Natural anticancer drugs have been shown to be both effective and safe in the treatment of cancer. Over 70% of the earth's surface and 95% of its tropical biosphere are covered by the oceans. 50% of the Earth's biodiversity, or 34 out of the 36 phyla, is made up of marine organisms. The majority of oceanic organisms are members of the marine flora, which also includes sponges, seaweed, algae, cyanobacteria, and marine fungi. These marine sources have created a significant opportunity for the discovery of novel anticancer compounds due to their taxonomically diverse and biological characteristics. Numerous marine compounds with potent anticancer properties have recently been identified, and clinical studies have demonstrated their effectiveness. The majority of them are sulfated polysaccharides and polyphenols, which are renowned for their powerful antioxidant, antitumor. Thus, the current chapter focuses on natural anticancer compounds and their derivatives that are undergoing clinical trials.

KEYWORDS: Cancer, Clinical trials, natural products, chemotherapeutic drugs, secondary metabolites..

INTRODUCTION:

According to projections, there will be roughly 6,00,920 cancer deaths and 16,88,780 new cancer cases in the USA in 2017. It is predicted that there will be 27 million new cases of cancer worldwide by 2030, along with 17 million deaths¹. The current cancer treatments, such as chemotherapy and radiotherapy, can be very taxing on patients and worsen their health. As a result, scientists are concentrating on using natural substances as cancer therapies. For thousands of years, various diseases have been treated with natural substances derived from plants.

Ancient China, Egypt, Greece, and India all used terrestrial plants as medicines². Although there are many medications on the market to treat cancer, no one medication has been found to be both completely effective and safe. As a result, research into the anticancer properties of natural lead compound constituents from plants, microbes, and marine fauna and flora has recently increased. Numerous naturally occurring substances and their derivatives have been found to be effective anticancer medications. More than 60% of clinically effective anticancer agents have been developed using natural compounds^3-4.

METHODS:

Materials:

A number of cancers, including leukemias, advanced testicular cancer lymphomas, breast and lung cancers, and Kaposi's sarcoma, are treated with these substances in combination with other medications⁵. There is a long history of using podophyllotoxin, a lignan isolated from Podophyllum peltatum, to treat warts and skin cancer. Due to its high toxicity, podophyllotoxin failed in clinical trials, but its semi-synthetic derivatives, such as etoposide and teniposide, have demonstrated anticancer properties with low toxicity. Etoposide and teniposide are currently used to treat lymphoma, bronchial, testicular, and other cancers⁶. Topoisomerase II, a crucial enzyme involved in the replication pathway of DNA during cell cycle progression, is inhibited by these substances⁷. The clinical status and mechanisms of action of plant-derived anticancer substances like alkaloids, terpenes, sterols, and phenols are discussed below⁸.

Other biologically and clinically significant properties, including antimicrobial, anti-inflammatory, anticoagulant, and photoprotective, have also been shown for compounds of marine origin⁹. Some marine organisms, like sponges, have been studied for their potential as anticancer agents because of their symbiotic relationships with actinomycete¹⁰. Numerous antitumor medications have been created by marine pharmaceutics over the past three decades¹¹. To produce new antitumor compounds, however, the marine environment has not been fully explored. It is primarily due to the gaps in this area. Even though there aren't many products made from marine sources on the market right now, the majority of them are still in the clinical trial and drug development stages^12-15. In 2007, medications derived from marine sources, including the marine alkaloid trabectedin, were made available for the treatment of cancer. Over the past ten years, reports of about 2500 metabolites with antiproliferative activity have been made. Below is a discussion of anticancer marine-derived compounds, their derivatives, and the clinical status of those compounds^16-20.

The marine invertebrate Bugula neritina is where bryostatins, a class of naturally occurring macrolides with significant therapeutic value, were first discovered. They typically have three remotely functionalized polyhydropyran rings and a 20-membered macrolactone core in common. The substitution at C7 and C20, as well as the placement of the c-lactone in the polyhydropyran ring at either C19 or C23, distinguish bryostatins from one another²¹. Dolastatins are pentapeptides that were first discovered in the 1970s in the Indian Ocean in the sea hare Dolabellaauricularia and later in the cyanobacterium Symploca, which has recently been given the name Caldorapenicillata. The most potent drug in this class, dolastatin 10, has an ED50 of 4.6 105 g/ml against murine PS leukemia cells²². Phase II clinical trials for the treatment of primary mediastinal large B-cell lymphoma and the treatment of DLBCL with vedotin linked to brentuximab and rituximab have been completed. In order to treat Hodgkin's lymphoma, malignant mesothelioma, and non-Hodgkin' lymphoma, patients are being enrolled in phase II clinical trials^23-28. The US clinical trial registry lists a large number of ongoing clinical trials using brentuximab linked to vedotin in combination with other monoclonal antibodies to treat lymphoma (NIH).A tetrapeptide with an epoxy-b-aminoketone moiety called epoximicin was discovered in an unidentified strain of actinomycetes. The first reports of its antitumor effects date back to 1992. Epoxomicin was enrolled in preclinical trials run by Bristol-Myers Squibb but was discontinued due to an unidentified mode of action. Epoxomicin is a proteasome inhibitor, as later discovered by Crews' team at Yale University. After the discovery of its mechanism of action, several epoxomicin derivatives were created²⁹.

Major phytochemicals used for ameliorating or preventing Cancer

Natural Marine Anticancer Compounds and Their Derivatives in Clinical Trials

Class	Compound	Source	Mode of action	Clinical trial stage
Bryostatins	Bryostatin 1	Bugula neritina (bryozoan)	PKC inhibition and apoptosis	Advanced pancreatic, metastatic prostate, and kidney cancer – phase II (c)
Bryostatins	Bryostatin 1	Bugula neritina (bryozoan)	PKC inhibition and apoptosis	HIV-related lymphoma, metastatic solid tumors – phase I (c)
Dolastatin	Dolastatin 10	Dolabellaauricularia/ Symploca sp.	Microtubule inhibition	Metastatic pancreatic cancer, kidney and ovarian cancers, lymphoma – phase II (c), metastatic soft tissue sarcoma – phase II (c)
	Soblidotin/auristatin (TZT-1027)	Synthetic derivative of dolastatin 10	Microtubule inhibition	Metastatic soft tissue sarcoma and NSCLC – phase II (c)
	Synthadotin/tasidotin	Synthetic derivative of dolastatin 15	Mitosis and topoisomerase inhibition	Malignant melanoma – phase I/II (c)
	Synthadotin/tasidotin	Synthetic derivative of dolastatin 15	Mitosis and topoisomerase inhibition	NSCLC and prostate cancer – phase II (c) solid tumors – preclinical (c)
	Monomethyl auristatin E (MMAE)/Vedotin	Synthetic variant of auristatin (as ADC)	Microtubule inhibition	Lymphoma – phase II melanoma, triple-negative breast cancer – phase III and solid tumors – phase I/II
	Monomethyl auristatin F (MMAF)	Synthetic variant of auristatin (as ADC)	Microtubule inhibition	Relapsed/refractory multiple myeloma – phase I (r) and hematologic malignancies – phase I
Ecteinascidin	Trabectedin (ET-743)	Ecteinascidia turbinate	Double-strand DNA damage by minor groove binding	Solid tumors, pediatric cancers – phase II (r)
				Breast and advanced prostate cancer – phase II (c)
				Soft tissue sarcoma and ovarian cancer – approved
	Lurbinectedin (PM01183)	Structural variant of trabectedin	Double-strand DNA damage by minor groove binding	Osteosarcoma – phase II (c) NSCLC – phase III (r) and advanced solid tumors, metastatic breast cancer – phase II (r)
	Zalypsis (PM 00104)	Structural variant of trabectedin	DNA minor groove binding	Metastatic Ewing’s family of tumors – phase II (c)
Kahalalide	Kahalalide F	Elysia rufescens/ Bryopsis sp.	Lysosome target and promotion of oncosis	NSCLC – stage IIIB/IV – phase II
Kahalalide	Elisidepsin (PM02734)	Synthetic derivative of kahalalide F	Oncosis and necrosis promotion	Advanced malignant solid tumors – phase I (c)
Aplidine	Aplidine	Aplidium albicans	Apoptosis and angiogenesis inhibition	Refractory/relapsed multiple myeloma – phase III (r), leukemia, lymphoma – phase II (c) advanced solid tumors – phase I (r)
Epoxomicin	Carfilzomib	Synthetic derivative of epoxomicin	Proteasome inhibition	Multiple myeloma – approved NSCLC; ovarian, renal, and prostate cancers; and hematological malignancies – phase I/II (r)
Halichondrin	Eribulin mesylate (E7389)	Synthetic derivative of halichondrin B	Microtubule inhibition	Metastatic breast cancer, liposarcoma – approved NSCLC, advanced solid tumors, prostate cancer – phase II (c), soft tissue sarcomas, pediatric, cervical cancers – phase I/II (r)
Salinosporamides	Salinosporamide A (NPI-0052)	Salinispora sp. (bacterium)	20 S proteasome inhibition	Grade IV malignant glioma – phase I/II (r)
Salinosporamides	Salinosporamide A (NPI-0052)	Salinispora sp. (bacterium)	20 S proteasome inhibition	Solid tumors, lymphomas, leukemia, multiple myeloma, pancreatic cancer, melanoma, NSCLC – phase I (c)
Cytarabine	Ara-C	Cryptotheca crypta	DNA synthesis inhibition	AML, ALL and CML – approved meningeal metastasis of breast cancer – phase III (r), medulloblastoma and metastatic solid tumors – phase II (r)
	Gemcitabine	Derivative of cytarabine	DNA synthesis inhibition	Metastatic breast, ovarian, pancreatic cancers, and NSCLC – approved
	Gemcitabine	Derivative of cytarabine	DNA synthesis inhibition	Urothelial cancer – phase III (r), T-cell lymphoma, biliary tract cancers, and metastatic colorectal cancer – phase II (r), solid tumors and bladder cancer – phase I (r)
Halimide	Plinabulin (NPI-2358)	Aspergillus sp.	Microtubule inhibition	Metastatic NSCLC – phase III (r) and advanced solid tumors – phase II/III (r)
Hemiasterlin	E7974	Hemiasterellaminor sponge	Microtubule inhibitor	Solid tumors – phase I (c)

CONCLUSION:

The findings of this systematic review indicate that using herbal natural compounds. The clinical trials for cancer therapy have made extensive use of natural substances and their derivatives with anticancer properties. According to the NIH or the relevant EU clinical trial database, the current status of natural compounds in clinical trials and their natural sources was documented. Researchers or clinicians can choose the natural compounds of their interest for additional research or clinical use by using the information provided in this chapter to inform them of the compounds' anticancer properties, mechanisms of action, and clinical trial status. In contrast to synthetic compounds, which are dangerous and toxic to normal cells as well as cancerous cells, the main benefit of using natural compounds in anticancer therapy is that they are safe and less toxic. Vinblastine, vincristine, and taxol, which come from plants; dolastatin 10, cytarabine, and aplidine, which come from marine life; and bleomycin, doxorubicin, and dactinomycin, which come from microorganisms, are some of the most effective naturally occurring anticancer medications. Numerous bioactive compounds that have received clinical approval have been contributed by plants. Despite their contribution, the top pharmaceutical companies significantly reduced screening for bioactive lead molecules in plants for more than a decade, favoring combinatorial chemistry instead, which allows for the synthesis of libraries of millions of compounds. Furthermore, it took a lot of time and effort to characterize the lead molecules in plant extractions^29-33.

CONFLICT OF INTEREST:

The author has no conflicts of interest.

ACKNOWLEDGMENTS:

The authors would like to thank NCBI, PubMed and Web of Science for the free database services for their kind support during this study.

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Received on 30.12.2022 Modified on 20.03.2023

Asian J. Pharm. Tech. 2023; 13(3):235-239.

DOI: 10.52711/2231-5713.2023.00042