Abstract
Dolastatin 10 (Dol-10), a leading marine pentapeptide isolated from the Indian Ocean mollusk Dolabella auricularia, contains three unique amino acid residues. Dol-10 can effectively induce apoptosis of lung cancer cells and other tumor cells at nanomolar concentration, and it has been developed into commercial drugs for treating some specific lymphomas, so it has received wide attention in recent years. In vitro experiments showed that Dol-10 and its derivatives were highly lethal to common tumor cells, such as L1210 leukemia cells (IC50 = 0.03 nM), small cell lung cancer NCI-H69 cells (IC50 = 0.059 nM), and human prostate cancer DU-145 cells (IC50 = 0.5 nM), etc. With the rise of antibody-drug conjugates (ADCs), milestone progress was made in clinical research based on Dol-10. A variety of ADCs constructed by combining MMAE or MMAF (Dol-10 derivatives) with a specific antibody not only ensured the antitumor activity of the drugs themself but also improved their tumor targeting and reduced the systemic toxicity. They are currently undergoing clinical trials or have been approved for marketing, such as Adcetris®, which had been approved for the treatment of anaplastic large T-cell systemic malignant lymphoma and Hodgkin lymphoma. Dol-10, as one of the most medically valuable natural compounds discovered up to now, has brought unprecedented hope for tumor treatment. It is particularly noteworthy that, by modifying the chemical structure of Dol-10 and combining with the application of ADCs technology, Dol-10 as a new drug candidate still has great potential for development. In this review, the biological activity and chemical work of Dol-10 in the advance of antitumor drugs in the last 35 years will be summarized, which will provide the support for pharmaceutical researchers interested in leading exploration of antitumor marine peptides.
Highlights
The living environment of marine organisms is different from that of terrestrial creatures, and the peptide secondary metabolites of the former have special structures and provide bioactive components distinct from the latter [1,2,3]
Overexpression of Bcl-2 is common in small cell lung cancer (SCLC), and Dolastatin 10 (Dol-10) has the ability of inducing Bcl-2 phosphorylation to induce apoptosis in SCLC cell lines and xenografts
The results showed that the growth of four SCLC cell lines (NCI-H69, NCI-H82, NCI-H446, and NCI-H510) was strongly inhibited through Bcl-2 phosphorylation triggered by Dol-10 (IC50 = 0.032–0.184 nM) [37]
Summary
The living environment of marine organisms is different from that of terrestrial creatures, and the peptide secondary metabolites of the former have special structures and provide bioactive components distinct from the latter [1,2,3]. A series of antitumor polypeptides with high biological activity have been isolated from various marine organisms, such as hemiasterlins, cryptophycins, vitilevuamide, diazonamide, etc. Compared with traditional small molecule inhibitors, marine peptides present high activity, strong targeting, slmowalltomxioclietycu, eleasiynhtribanitsomrse,mmbarrainnee apbespotripdteisonp,raensednot whingha wacitdiveirtya,nsgteroonfgbitoalroggeitcianlga,cltoivwittoiexsic, istuy,cheaassyatnratintusmmeomr, barnatni-einafblasmormptaitoonr,ya, nandtiovwirnusa, awniddeanratiningfeecotfiobnio. S, isnicneceDoDlo-1l0-1w0 awsafisrsftirdsitsdcoisvceorveder, eitds,biitoslobgioicloalgaiccatilvaitcytiwviatys mwoarsempotreenpt tohtaent tthhoasne othf omsoesot fknmoowsnt kantoiwcancaenr tdicruangcse(rmdurruingesP(SmlueurikneemPiaS clelulsk,eEmDi5a0 c=e4ll.s6, ×ED1500−=5 4μ.g6/×m1L0)−,5 sμogi/tmhLad), asottriatchtead eaxttreancstievde eaxttteenntsiiovne iantttehnetifioenldinofthaentficealdncoefr arensteicaarncche.rInreisneavrictrho. TZT-1027 (Soblidotin) entered the phase I clinical trial, the main toxicity. TZT-1027 (Soblidotin) entered the phase I clinical trial, the main toxicity and neutropenia were observed, and the dosage level was insufficient to achieve clinical effiacnadcyne[4u5tr,4o6p]e. ESfifneccet oafcDcoulm-1u0,laittewdarsestepnetciuolnatiendctehllastathnedahdigmhinaifsftirnaittiyonbisncdhienmg ewwitohutludbiunltienrfmerieghwtiathffethcte tchlientihcaelreavpaleuuattiicoenffreecstuoltfs,Daonld-1i0n,fiutswioansasdpmeciunliasttreadtitohnawt tahsesaudpmeriinoirsttorabtoiolunssacdhmemineiswtroautilodnin[4t8e,r4f9e]r.e Fwuritthhetrhmeocrlien, itcoapl erovvaildueatrieoansorensaublltes,gauniddainncfue sfioornclaidnmicainl iasptrpalticioantiowna, sansudpeenrsiourretothbeosluafseatydamndineisffteracttiivonen[e4s8s,4o9f].cFhuermthoetrhmeroarpe,y,tothperopvhiadremreaacsookninabetliecgs,upidhaanrmceafcoordcylinnaicmalicasp,ptolixcaictiitoyn, , and drug resistance of Dol-10 had been explored in preclinical and phase I clinical trial. All of the above investigations will be elaborated through the following sections
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