Sulfonoquinovosyl diacylglyceride selectively targets acute lymphoblastic leukemia cells and exerts potent anti-leukemic effects in vivo
Authors: Chetan Kumar Jain
Madhumita Bhattacharyya
Sukdeb Banerjee
Susanta Roychoudhury
Hemanta Kumar Majumder
Saikat Chakrabarti
Nirup Bikash Mondal
Subeer S Majumder
Bhola Shankar Pradhan
Journal: Scientific Reports (2015)
Discipline: Multidisciplinary
Keywords: DNA topoisomerase II inhibitors; acute lymphoblastic leukemia; chemotherapy; cardiotoxicity; secondary malignancies
Affiliations: 1] Infectious Diseases and Immunology Division, CSIR-Indian Institute of Chemical Biology, 4, Raja S.C. Mullick Road, Jadavpur, Kolkata-700032, India [2] Cancer Biology and Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, 4, Raja S.C. Mullick Road, Jadavpur, Kolkata-700032, India., Division of Embryo Biotechnology, National Institute of Immunology, New Delhi, 110067, India., Chemistry Division, CSIR-Indian Institute of Chemical Biology, 4, Raja S.C. Mullick Road, Jadavpur, Kolkata-700032, India., Structural Biology and Bioinformatics Division. CSIR-Indian Institute of Chemical Biology, 4, Raja S.C. Mullick Road, Jadavpur, Kolkata-700032, India., Cancer Biology and Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, 4, Raja S.C. Mullick Road, Jadavpur, Kolkata-700032, India., Infectious Diseases and Immunology Division, CSIR-Indian Institute of Chemical Biology, 4, Raja S.C. Mullick Road, Jadavpur, Kolkata-700032, India.

Abstract:  DNA topoisomerase II inhibitors e.g. doxorubicin and etoposide are currently used in the chemotherapy for acute lymphoblastic leukemia (ALL). These inhibitors have serious side effects during the chemotherapy e.g. cardiotoxicity and secondary malignancies. In this study we show that sulfonoquinovosyl diacylglyceride (SQDG) isolated from Azadirachta indica exerts potent anti-ALL activity both in vitro and in vivo in nude mice and it synergizes with doxorubicin and etoposide. SQDG selectively targets ALL MOLT-4 cells by inhibiting catalytic activity of topoisomerase I enzyme and inducing p53 dependent apoptotic pathway. SQDG treatment induces recruitment of ATR at chromatin and arrests the cells in S-phase. Down-regulation of topoisomerase I or p53 renders the cells less sensitive for SQDG, while ectopic expression of wild type p53 protein in p53 deficient K562 cells results in chemosensitization of the cells for SQDG. We also show that constant ratio combinations of SQDG and etoposide or SDQG and doxorubicin exert synergistic effects on MOLT-4 cell killing. This study suggests that doses of etoposide/doxorubicin can be substantially reduced by combining SQDG with these agents during ALL chemotherapy and side effects caused can be minimized. Thus dual targeting of topoisomerase I and II enzymes is a promising strategy for improving ALL chemotherapy. 

Retracted: No

PubPeer comments:
 The Methods state that  Protocols for the experiments with nude mice were approved by the Institutional Animal Ethics Committee of NII. If this is true, then the researchers are not at fault here. , 
 #2 The **journal** is arguably at fault for publishing torture porn. , 
 #2 In my opinion, Pseudobryomima, the authors are very much at fault. Ignorance is no excuse. Still, a problem shared is a problem halved, as they say. What exactly, though, did the Ethics Committee approve? If the submitted protocol stated that it would follow international standards of laboratory animal care, then only the authors are to blame for not doing so. On the other hand, if the protocol stated that the end points would be ginormous, ulcerous, xenografts, then the Ethics Committee might as well resign en masse. I doubt we will get to see the text of the protocol that was approved, however. Manuscripts at Scientific Reports are handled by associated editors who are, in the main, practicing scientists. Perhaps not all have read animal care guidelines? It seems clear that the journal does not pre-screen for ethical violations. Presumably it also makes no effort to train the handling editors in research ethics and or provide them with access to research ethics guidelines. There canu2019t be one standard for Europe, where the journal is based, and lower standards for everywhere else. What they publish must reach European standards or be higher. Iu2019m curious as to whether the OAC will be returned when the paper is retracted. I believe that the vastly profitable NPG group can afford it. As mentioned, the evidence would suggest that Nature Publishing Group do not train their journal editors to recognise ethical violations. Perhaps the senior management do not think that it is relevant to their business model. But then a fish rots from the head. , 
 So it turns out that the Open Access Charge for this ethically challenged article with the largest known xenograft - distastefully decorated with open sores as it is - helps to pay the interest on Springer-Natureu2019s **3 billion euro debt** https: www.nytimes.com reuters 2018 05 08 business 08reuters-springer-nature-ipo.html Given that NPG and Springer have been and still are highly profitable publishers, how the blazes did they get saddled with this massive liability? Government funded research around the world doesnu2019t just pay for the actual cost of publishing with this outfit. And it doesnu2019t also only stump up for the 551 million Euros in annual profits. All these governments are also paying the interest on Springer Natureu2019s debts on behalf of the owners which include a private equity company. Well, itu2019s nice work if you can get it! Of course this all happened before https: www.businessinsider.de why-toys-r-us-is-closing-stores-2018-3?r=US IR=T Do we have a new Sores R Us in the making? At any rate, I now donu2019t think that they can afford to return the OAC on retracted papers after all. , 
 Ah, so there does appear to be a larger published xenograft than this NPG special. Itu2019s in Cancer Res., 2000. It was noted at PubPeer three years ago https: pubpeer.com publications 8CE9157DB66BB5ED60FEB31C6AF21B Hideous, just hideous , 
 #5 The NYT article that Condylocarpon Amazonicum alludes to cannot be found. Linking to that page reveals the following message  Page No Longer Available This news-agency article is no longer available on nytimes.com. Even the internet archive has no archived copy. This needs to be addressed and or corrected. Did this article actually exists, and if yes, why does it no longer exist? , 
 #7 Could it have been this article? https: www.reuters.com article us-springer-nature-ipo weak-demand-forces-springer-nature-to-cancel-3-2-billion-float-at-last-minute-idUSKBN1I91FU , 
 Those who do not learn from history are condemned to repeat it. Even if it is a failure to learn from their very own history: https: pubpeer.com publications 21753854 And now Iu2019ve seen something that I wish I had not. It will stay with me. It gave me a nightmare last night. If you are of sensitive disposition, look away now or you may be similarly afflicted. How often will we need to point out to UK-based Nature Publishing Group that there are in fact guidelines for humane treatment of nude mice bearing tumourous xenografts. If I can find UK-based guidelines, why canu2019t NPG? https: www.ncbi.nlm.nih.gov pmc articles PMC2883160 So, either the mouse at left is very, very small or itu2019s xenografted tumour substantially exceeds 1.5 cm. There is even a clue: Sharp-eyed readers will (unlike the editor, the reviewers and the copy editors) note the ruler placed alongside. Looks like this tumour is a good 3 cm in length. And what about the ulcerating necrosis that has eaten right through the skin? ![image] I worry that the poor mouse could no longer exercise on its wheel. Indeed, in my nightmare, I had this ghastly vision that every time it got up to speed, the canceru2019s huge and eccentric mass meant that the mouse flew out of the right side of the wheel to be splattered against the side of its cage. As with NPG, in my nightmare the mouse did not learn from history and was condemned to repeat it. Edited 4-3-18 to spell xenograft correctly. It remains incorrect in the linked image , 
 On March 31st 2021, Scientific Reports wrapped up the investigation of these giant mouse xenografts. ![image] Apparently, they were euthanised when signs of ulceration were observed. Unless my eyes are deceiving me, they canu2019t have been inspected for quite a few days - given that all three are, in fact, ulcerated. Or would that be necrotised? Furthermore there is no need whatsoever for a xenografted tumour ever to reach 2 cm mean length. It just means that the experiment has been allowed to run for too long and therefore was probably poorly designed. The *Animal Ethics Committee of CSIR-Indian Institute of Chemical Biology (Kolkata, India)* might like to review their guidelines as regards cancer xenografts into mouse recipients. And the animal house should keep a proper eye on the condition of its mice. I see that, by pure coincidence, NAR retracted a 2003 article from this very lab on June 4th 2021 due to *u201cstrong evidence of image manipulationu201d*. https: pubmed.ncbi.nlm.nih.gov 33959779 As a result of concerns being posted by sharp-eyed peeps on PubPeer https: pubpeer.com publications 34E9446142CBE8FCD55311F1EB9C1C And there are also some interesting looking FACS plots that have been discussed here https: pubpeer.com publications D89F3D26CEE181F2DDDF9A1E66F6D8 ,